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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity


Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The applicant for an ANDA in the USA has to submit data of several stability tests. The FDA guidance on this topic coming into force last year left open some issues, however, that now are clarified with a questions and answers document published lately.

Read more.,8489_n.html

Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity

The FDA Guidance for Industry with the title “ANDAs: Stability Testing of Drug Substances and Drug Products” was published in the Federal Register on 20 June 2013 (also see our News dated 1 August 2013) and is addressed to applicants for ANDAs in the USA. This guidance describes the stability data the FDA expects in the documents submitted for an ANDA and is rather short having only five pages. As expected, the FDA received vast amounts of questions concerning certain problems that were not answered clearly in the guidance. Therefore, the Agency was prompted to address these questions in a questions and answers document. This document has the title “ANDAs: Stability Testing of Drug Substances and Drug Products – Question and Answers” and was published on the FDA “Guidance”-Website in May 2014.

The questions and answers are addressed in the following five chapters:

  • A. General
  • B. Drug Master File
  • C. Drug Product Manufacturing and Packaging
  • D. Amendments to Pending ANDA Application
  • E. Stability Studies

Some of the case studies discussed in these chapters are rather complex and therefore are answered in detail. In the following some questions and answers are listed for each chapter by way of example.

A. General
Question: Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?
Answer: Yes. An ANDA applicant should submit this data. However, if 6 months of accelerated data show a significant change or failure of any quality attribute, the applicant should also submit 6 months of intermediate data at the time of submission.

Question: In the event of an adverse change of quality attributes at accelerated condition: When do intermediate stability studies need to be initiated?
Answer: An ANDA applicant should start accelerated, intermediate, and long-term stability studies at the same time so the data are available at the time of submission, if needed.

Question: During the review cycle, will the application need to be updated with 12 months of long-term data?
Answer: Yes. FDA will grant a shelf life period to the drug product of two times the available long-term data at the time of approval (up to 24 months). This is on condition, however, that the submitted stability data are satisfactory, and data evaluation and appropriate commitments are provided. With this the authority follows a recommendation of the Guideline ICH Q1E.

B. Drug Master File
Question: How many months of long-term and accelerated data are required when a “Completeness Assessment” is performed on the Drug Master File?  Also, what should the stability section contain for a Completeness Assessment?
Answer: To pass the Completeness Assessment, the DMF should include the stability protocol and commitments. It also should contain data demonstrating that stability studies have started.  The initial and one additional time point for the accelerated studies and long-term studies are sufficient. If the DMF does not meet the requirements for a successful assessment (see the following question/answer) the DMF holder must hand in updated stability data later.

Question: Are stability data from three current good manufacturing practice (CGMP) batches required to be filed in the DMF to support the active pharmaceutical ingredient retest date? How many months of long-term and accelerated data are required for pilot scale batches?
Answer: Yes. The DMF should contain data from stability studies on at least three primary batches of the API (these batches should be made under cGMP conditions) and the batches should be manufactured to a minimum of pilot scale (also see ICH Q1A(R2)).
The FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term data for the pilot scale batches to be submitted for a full scientific review of the DMF.  Additional long-term data for all three batches, as the data becomes available through the proposed retest period, should be submitted as an amendment.

C. Drug Product Manufacturing and Packaging
Question: What is the Agency’s position on using different lots of APIs and/or packaging materials?  How many API lots should be used in the manufacture of finished product lots used to support the ANDA?
Answer: It is not necessary to use different lots of packaging material, except in cases where the packaging material could affect drug product performance and/or delivery.
A minimum of two lots of the drug substance should be used to prepare the three primary batches of drug product. For nasal aerosols and nasal sprays, you should use three different lots of drug substance.

Question: Should the small scale batches be packaged with commercial equipment?  Is it acceptable to package using research equipment?
Answer: Yes. Small scale batches should be packaged with commercial equipment.  Anyway, the packaging equipment should be similar to that proposed for use prior to market distribution.
No, it is not recommended to package small scale batches using research equipment or by hand. …

D. Amendments to Pending ANDA Application
Question: What are the recommendations for amendments and responses filed to pending ANDAs after issuance of the final FDA stability guidance?
Answer: All amendments submitted to pending ANDAs after the effective date of the final FDA stability guidance will be held to the standards in place concerning stability data at the time of the original ANDA submission, unless there is a concern with the submitted stability data.

E. Stability Studies
Question: Can the Agency clarify expectations for the storage positions for products placed into the stability program?
Answer: For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into an inverted (or horizontal) position and an upright position. For routine stability studies, the applicant should pick the worst case orientation for the study.

Question: Can the Agency clarify expectations around the number of batches to support tests such as preservative effectiveness and extractable leachable testing?
Answer: One of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed shelf life.  The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies.
Extraction/leachable studies are generally one-time studies. However, if multiple types of containers/closures are employed for packaging, then additional studies could be recommended.

The FDA tries to clarify the cases described in this Q&A document as clear and as much in detail as possible. In doing so the Agency complements its declarations by numerous indications concerning the provisions in the ICH guidelines Q1A(R2), Q1D, Q1E and in 21 CFR Part 211. Thereby, this very important and updated document covers most situations with regard to stability testing for ANDAs.



How to Handle Drug Polymorphs… Case Study of Trelagliptin Succinate

Pharmaceutical API Polymorphs… case study of Trelagliptin
CASE STUDY WITH..Compound I having the formula
Figure imgf000073_0001
Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the solid-state as part of an approved dosage form, can exist in such diverse solid forms as polymorphs, pseudopolymorphs, salts, co-crystals and amorphous solids. Various solid forms often display different mechanical, thermal, physical and chemical properties that can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the drug.
Hence, a thorough understanding of the relationship between the particular solid form of an active pharmaceutical ingredient (API) and its functional properties is important in selecting the most suitable form of the API for development into a drug product. In past decades, there have been significant efforts on the discovery, selection and control of the solid forms of APIs and bulk drugs.

If you’re involved in late drug discovery, API manufacture, drug product formulation, clinical material production, or manufacture of final dosage form, a basic understanding and awareness of solid form issues could save you a great deal of difficulty, time, and money during drug development.

What is polymorphism?
Polymorphs are crystalline materials that have the same chemical composition but different molecular packing. The concept is well demonstrated by the different crystalline forms of carbon. Diamond, graphite, and fullerenes are all made of pure carbon, but their physical and chemical properties vary drastically. Polymorphs are one type of solid form. Other solid form types include solvates, hydrates, and amorphous forms.
Solvates are crystalline materials made of the same chemical substance, but with molecules of solvent regularly incorporated into a unique molecular packing. When water is the solvent, these are called hydrates. An amorphous form of a substance has the same chemical composition, but lacks the long-range molecular order of a crystalline form of the same substance. Many organic and inorganic compounds, including APIs, can exist in multiple solid forms.
Some APIs may have only one or two known solid forms. Others may exist in twenty different forms, each having different physical and chemical properties.
Solid form screening, including salt, polymorph, cocrystal and amorphous solid dispersions, is vitial for successful pharmaceutical development. With an increase in the size and complexity of the molecules that enter into drug development, companies face a larger number of compounds that are either poorly soluble, difficult to crystallize or problematic with respect to desired physical chemical properties hindering successful drug development.
Crystallics has an extensive track record in executing solid state research studies and its research team has a broad expertise in identifying new crystal forms as well as in solving problems related to polymorphism and crystallization.

Investigational new drug, writing an application for clinical trial authorization, permission marketing …The control of polymorphism in drug candidates is now ubiquitous.


READ………….An Overview of Solid Form Screening During Drug Development,


When addressing the subject of polymorphism, the first reference that comes to mind is that of the occurred during the manufacture of ritonavir incident. Abbott molecule inhibitor of HIV protease marketed as Norvir, is a cautionary example of the challenges of polymorphism. 

Indeed, during the production of ritonavir in 1997, a new polymorph unmarked emerged. Its precipitation and unexpected outbreak led to the cessation of the production of Norvir and seriously compromise the process. The incident has deeply marked the pharmaceutical industry.

It is ironic that the process used to discover pharmaceutical drug targets is the same one that decreases the actual efficacy of those drugs once ingested. If you remember from basic chemistry, there are compounds that exist in highly ordered crystalline states and those that remain in amorphous form.

The discovery of drug targets has often been accomplished through X-ray crystallography, which requires a sample (for example, of a defective enzyme linked to cancer or high cholesterol) to be crystallized so that the diffraction patterns can be made sense of. Scientists may spend years trying to crystallize one molecule or compound so that they can identify regions that, for example, may be blocked by pharmaceuticals.

However, when it comes to the molecular arrangement of those pharmaceuticals, crystallization actually decreases their bioavailability and solubility. Thus, it may be better for these drugs to be in amorphous form. Pierric Marchand, general manager of the company Holodiag, dedicated to the study and characterization of solid state, summarizes that ” today, it is not reasonable to not worry about the problem of polymorphism ” .

” In recent years, manufacturers have realized the essential side of expertise , “says Jean-Rémi David, commercial director Calytherm. The services company specializing in the field of physico-chemical analysis, based in Herault, has just relocated last year in supporting pharmaceutical development to meet demand. ” This is a concern for all deal with potential impacts on the effectiveness or the formulation , “says Stéphane Suchet, quality manager in the group of fine and specialty chemicals Axyntis.

Polymorphic forms are the amorphous and crystalline forms such as hydrate or solvate forms. When a molecule of interest exists in polymorphic forms, it is called polymorphism, according to the definition of the FDA (Food and Drug Administration).

Polymorphism is present at all stages of development of a drug from research to marketing. ” Keep in mind that organic molecule loves to polymorphism , “says Marchand Pierric. However, for a marketing authorization for example, must learn the criteria for the polymorphism of the molecule. ” In terms of the formulation, for example we can check whether the selected polymorphism is unchanged , “explains Pierric Marchand.

A significant influence on several levels  Because the consequences of polymorphism are multiple. ” They are at three levels: bioequivalence, manufacturability and stability “lists Fabienne Lacoulonche, founder and scientific director of Calytherm.In terms of bioequivalence, different polymorphic forms may have different properties of solubility and dissolution rate … ” For poorly soluble active ingredients, you can have much more bioavailable than other crystalline forms , “Fabienne Lacoulonche information.

In terms of manufacturability, some parameters such as temperature, moisture can lead to changes in the crystalline form. ” The complexity is to anticipate changes polymorphism, both at laboratory scale, pilot and industrial , “adds the founder of Calytherm. Finally, polymorphism plays on stability. Active ingredient or finished product, are subjected to stability studies in this direction. ” When the molecule is identified, we try to highlight the existence of several forms of polymorphism, explains Stéphane Suchet (Axyntis) 

When developing a new substance, the assessment is systematic . ” Isolation of crystals from a screening is carried out in different solvents by various analytical techniques. Ideally, it will be concluded the absence of polymorphism. ” But if different polymorphic forms are present, we rework the terms of our crystallization process to control the formation of the same polymorph reproducibly ideally form the thermodynamically more stable , “says Stéphane Suchet. X-ray diffraction and other thermal analysis ”

The ICH guidelines provide decision trees to guide the industry in controlling polymorphism says Fabienne Lacoulonche (Calytherm.) We use it for writing the CTD (Common Technical Document) .

“Polymorphism is a phenomenon” complex and difficult to control, because the crystallization is dependent on many parameters , she develops. must understand the maximum . ” For this, several analytical methods are available to industry. The main technique is the X-ray diffraction ” It is a robust, rapid, which allows to characterize the different polymorphs , “summarizes Pierric Marchand (Holodiag).Non-destructive, it can work both on small quantities on large samples. Temperature and atmosphere are controlled, and analytical capabilities are broad.

But if this technique indispensable allows for routine and development, it is not sufficient in itself. Just to add a battery of additional tests, thermal analysis. ” It takes coupling methods “ confirms Fabienne Lacoulonche (Calytherm). The X-ray diffraction is a method of choice, but sometimes it is not sufficient.

The coupling with a thermal analysis method (technical ATG, or DSC thermal analysis, differential scanning calorimetry or thermomicroscopique) allows to distinguish between two polymorphic whose RX diffractograms obtained are comparable.

TGA can be coupled with IR or mass spectrometry, DSC with RX. Raman spectroscopy is also part of complementary methods. ” The difficulty increases when we want to characterize the shape of the active ingredient in the finished product , says Fabienne Lacoulonche. example, by X-ray diffraction, the peaks related to the active ingredient in the diffractogram of the finished product may be masked by those excipients: it is then necessary to use other methods, such as Raman microscopy. “In general, a single method of analysis is not sufficient to characterize the polymorphism of an active substance in the active substance or finished product: the complementarity of different methods that will conclude precisely on the polymorphism of a crystalline substance.

In addition, ” the diffractometer remains an expensive device, which requires installation in an air-conditioned and a cooling room , “says Marchand Pierric (Holodiag). To this is added the need to have expertise and qualified personnel to carry out the analyzes. ” We must master these techniques and the ability to interpret the results , “says Jean-Rémi David (Calytherm). However, polymorphism is a “problem well under control , “said Stéphane Suchet (Axyntis),” systematically evaluated although it is however not always immune to miss a polymorphic form, knowing that the screening performed in the development can never be completely comprehensive … ”


FDA may refuse to approve an ANDA referencing a listed drug if the application contains insufficient information to show that the drug substance is the “same” as that of the reference listed drug. A drug substance in a generic drug product is generally considered to be the same as the drug substance in the reference listed drug if it meets the same standards for identity.

In most cases, the standards for identity are described in the USPalthough FDA may prescribe additional standards when necessary. Because drug product performance depends on the product formulation, the drug substance in a proposed generic drug product need not have the same physical form (particle size, shape, or polymorph form) as the drug substance in the reference listed drug. An ANDA applicant is required to demonstrate that the proposed product meets the standards for identity, exhibits sufficient stability and is bioequivalent to the reference listed drug.


FDA PRESENTATION……polymorphs and co-crystals – ICDD      Regulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals.. THIS IS A MUST READ ITEM

Over the years FDA has approved many generic drug products based upon a drug substance with different physical form from that of the drug substance in the respective reference listed drug (e.g., warfarin sodium, famotidine, and ranitidine). Also many ANDAs have been approved in which the drug substances differed from those in the corresponding reference listed drugs with respect to solvation or hydration state (e.g., terazosin hydrochloride, ampicillin, and cefadroxil). Several regulatory documents and literature reports (67-69) address issues relevant to the regulation of polymorphism.

The concepts and principles outlined in these are applicable for an ANDA. However, certain additional considerations may be applicable in case of ANDAs. Often at the time FDA receives an ANDA a monograph defining certain key attributes of the drug substance and drug product may be available in the Unites States Pharmacopoeia (USP). These public standards play a significant role in the ANDA regulatory review process and in case of polymorphism, when some differences are noted, lead to additional requirements and considerations.

This commentary is intended to provide a perspective on polymorphism in pharmaceutical solid in the context of ANDAs. It highlights major considerations for monitoring and controlling drug substance polymorphs and describes a framework for regulatory decisions regarding drug substance “sameness” considering the role and impact of polymorphism in pharmaceutical solids.

Since polymorphs exhibit certain differences in physical (e.g., powder flow and compactability, apparent solubility and dissolution rate) and solid state chemistry (reactivity) attributes that relate to stability and bioavailability it is essential that the product development and the FDA review process pay close attention to this issue.

This scrutiny is essential to ensure that polymorphic differences (when present) are addressed via design and control of formulation and process conditions to physical and chemical stability of the product over the intended shelf-life, and bioavailability/bioequivalence.

Most pharmaceuticals are distributed as solid doseages. In order to take action, they must dissolve in the gut and be absorbed into the blood stream. In many cases, the rate at which the drug dissolves can limit its effectiveness. Pharmaceutical compounds can be packed into more than one arrangement in the solid states known as polymorphs. Rapid and efficient methods of polymorph formation can be used to increase drug efficacy and shelf life.

Regulatory agencies worldwide require that, as part of any significant filing, a company has to demonstrate that it has made a reasonable effort to identify the polymorphs of their drug substance and has checked for polymorph interconversions. Due to the unpredictable behaviour of polymorphs and their respective differences in physicochemical properties, companies also have to demonstrate consistency in manufacturing between batches of the same product. Proper understanding of the polymorph landscape and nature of the polymorphs will contribute to manufacturing consistency.



Triclinic Labs approach to solid-state (solid form) screening and selection for optimal properties of an active pharmaceutical ingredient


READ………..High-throughput crystallization: polymorphs, salts, co-crystalsand solvates of pharmaceutical solids


“Crystalline”, as the term is used herein, refers to a material, which may be hydrated and/or solvated, and has sufficient ordering of the chemical moiety to exhibit a discernable diffraction pattern by XRPD or other diffraction techniques. Often, a crystalline material that is obtained by direct crystallization of a compound dissolved in a solution or by interconversion of crystals obtained under different crystallization conditions, will have crystals that contain the solvent used in the crystallization, termed a crystalline solvate. Also, the specific solvent system and physical embodiment in which the crystallization is performed, collectively termed crystallization conditions, may result in the crystalline material having physical and chemical properties that are unique to the crystallization conditions, generally due to the orientation of the chemical moieties of the compound with respect to each other within the crystal and/or the predominance of a specific polymorphic form of the compound in the crystalline material.

Depending upon the polymorphic form(s) of the compound that are present in a composition, various amounts of the compound in an amorphous solid state may also be present, either as a side product of the initial crystallization, and/or a product of degradation of the crystals comprising the crystalline material. Thus, crystalline, as the term is used herein, contemplates that the composition may include amorphous content; the presence of the crystalline material among the amorphous material being detectably among other methods by the composition having a discernable diffraction pattern.

The amorphous content of a crystalline material may be increased by grinding or pulverizing the material, which is evidenced by broadening of diffraction and other spectral lines relative to the crystalline material prior to grinding. Sufficient grinding and/or pulverizing may broaden the lines relative to the crystalline material prior to grinding to the extent that the XRPD or other crystal specific spectrum may become undiscernable, making the material substantially amorphous or quasi-amorphous. Continued grinding would be expected to increase the amorphous content and further broaden the XRPD pattern with the limit of the XRPD pattern being so broadened that it can no longer be discerned above noise. When the XRPD pattern is broadened to the limit of being indiscernible, the material may be considered no longer a crystalline material, but instead be wholly amorphous. For material having increased amorphous content and wholly amorphous material, no peaks should be observed that would indicate grinding produces another form.

“Amorphous“, as the term is used herein, refers to a composition comprising a compound that contains too little crystalline content of the compound to yield a discernable pattern by XRPD or other diffraction techniques. Glassy materials are a type of amorphous material. Glassy materials do not have a true crystal lattice, and technically resembling very viscous non-crystalline liquids. Rather than being true solids, glasses may better be described as quasi-solid amorphous material. “Broad” or “broadened”, as the term is used herein to describe spectral lines, including XRPD, NMR and IR spectroscopy, and Raman spectroscopy lines, is a relative term that relates to the line width of a baseline spectrum. The baseline spectrum is often that of an unmanipulated crystalline form of a specific compound as obtained directly from a given set of physical and chemical conditions, including solvent composition and properties such as temperature and pressure.

For example, broadened can be used to describe the spectral lines of a XRPD spectrum of ground or pulverized material comprising a crystalline compound relative to the material prior to grinding. In materials where the constituent molecules, ions or atoms, as solvated or hydrated, are not tumbling rapidly, line broadening is indicative of increased randomness in the orientation of the chemical moieties of the compound, thus indicative of an increased amorphous content. When comparisons are made between crystalline materials obtained via different crystallization conditions, broader spectral lines indicate that the material producing the relatively broader spectral lines has a higher level of amorphous material.

“About” as the term is used herein, refers to an estimate that the actual value falls within ±5% of the value cited. “Forked” as the term is used herein to describe DSC endotherms and exotherms, refers to overlapping endotherms or exotherms having distinguishable peak positions


Classes of multicomponent pharmaceutical materials. (a) Schematic of crystalline materials showing neutral and charged species. The red box indicates polymorphs are possible for all the multicomponent crystals contained within the box (adapted from Reference 7). (b) Schematic of amorphous solid dispersions showing binary, ternary, and quaternary possibilities for polymers and surfactants. Other solubilization techniques using cyclodextrins and phospholipids are included for completeness but have a different mechanism for solubilization when compared to polymer and surfactant systems.

The red box indicates that properties can change with water or solvent content. General methods for precipitating and crystallizing a compound may be applied to prepare the various polymorphs described herein. These general methods are known to those skilled in the art of synthetic organic chemistry and pharmaceutical formulation, and are described, for example, by J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure ” 4th Ed. (New York: Wiley-Interscience, 1992).

In general, a given polymorph of a compound may be obtained by direct crystallization of the compound or by crystallization of the compound followed by inter-conversion from another polymorphic form or from an amorphous form. Depending on the method by which a compound is crystallized, the resulting composition may contain different amounts of the compound in crystalline form as opposed to as an amorphous material.

Also, the resulting composition may contain differing mixtures of different polymorphic forms of the compound. Compositions comprising a higher percentage of crystalline content {e.g., forming crystals having fewer lattice defects and proportionately less glassy material) are generally prepared when using conditions that favor slower crystal formation, including slow solvent evaporation and those affecting kinetics.

Crystallization conditions may be appropriately adjusted to obtain higher quality crystalline material as necessary. Thus, for example, if poor crystals are formed under an initial set of crystallization conditions, the solvent temperature may be reduced and ambient pressure above the solution may be increased relative to the initial set of crystallization conditions in order to slow down crystallization. Precipitation of a compound from solution, often affected by rapid evaporation of solvent, is known to favor the compound forming an amorphous solid as opposed to crystals. A compound in an amorphous state may be produced by rapidly evaporating solvent from a solvated compound, or by grinding, pulverizing or otherwise physically pressurizing or abrading the compound while in a crystalline state.

Seven crystalline forms and one amorphous solid were identified by conducting a polymorph screen (Example 3). Described herein are Form A, Form B, Form C, Form D, Form E, Form F, Form G, and Amorphous Form of Compound I. Where possible, the results of each test for each different polymorph are provided. Forms A, C, D and E were prepared as pure forms. Forms B, F, and G were prepared as mixtures with Form A.
Various tests were performed in order to physically characterize the polymorphs of Compound I including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Fourier transform infrared spectroscopy (FT-IR), Fourier transform Raman spectrometry, linked thermogravimetric-infrared spectroscopy (TG-IR), solution proton nuclear magnetic resonance (1H-NMR), solid state 13carbon nuclear magnetic resonance (13C-NMR), and moisture sorption and desorption analysis (M S/Des).


Salt screening

Physicochemical properties of drug substances, such as solubility, dissolution rate, and physicochemical stability can be altered significantly by salt formation. Consequently, important properties of the drug product such as bioavailability or shelve life can be radically influenced. Crystallics’ technology platform for crystallization screening accommodates salt screening studies using only minimal amounts of drug substance while still performing a large number of experiments. High-throughput salt screening is used for both early phase salt selection studies and broad patent protection.

Salt selection – A powerful strategy for crystal form optimization

Pharmaceutical developers have focused efforts on finding and formulating a thermodynamically stable crystalline form with acceptable physical properties for a given compound. This is reasonable, given the need to avoid cascading from a meta-stable form to a more stable one in unpredictable fashion.

Occasionally certain physical properties, such as low aqueous solubility, are limiting to performance of the compound, leading to poor oral bioavailability or insufficient solubility for an injection formulation. One of the main strategies used to affect physical performance of a compound and one that is often employed by pharmaceutical scientists is the practice of salt selection (23). At least half of compounds in marketed products are in the form of a salt for one reason or another.

This fact alone speaks to the versatility of the salt selection approach. Salt forms of a pharmaceutical can have many benefits, such as improved stability characteristics, optimal bioavailability and aqueous solubility for an injectable formulation. Salts, like all other crystalline forms, are subject to polymorphism and solvate formation, thus requiring the same form identification studies as are needed for a neutral compound.

A remarkable example of co-optimization of properties is indinavir (HIV protease inhibitor), which is marketed as the sulfate salt ethanol solvate (24,25) The crystalline free base has variable oral bioavailability in dogs (26,27) and humans (28). While acidic solutions of the base compound showed good oral pharmacokinetics, the stability of the drug in acidic solution is not consistent with a product (26). Therefore, the discovery of the salt form ensured both shelf stability and robust bioavailability performance. The salt selection strategy is limited in two ways.

First, salt formation relies on the presence of one or more ionizable functional groups in the molecule; many drugs and development compounds lack this feature.

Second, our ability to predict a priori whether a given compound will form a crystalline salt (or salts) is non-existent. The ability to actively identify crystalline salt forms has been confined to manual empirical evaluation using multiple salt formers for a given acid or base. Recently advances have been made in the area of high-throughput salt selection and crystal engineering strategies associated with salt formation (14,29-32).

In one case, we have advocated the simultaneous assessment of polymorphism as a way to help rank the developability of different crystalline salts (14). While salt forms will continue to have a prominent place in pharmaceutical science, the need for enhanced productivity dictates that every advantage must be sought to aid the design of an appropriate crystalline form of an active molecule.

Specifically, the ability to design scaffolds into crystalline forms will enhance our capacity to convert interesting molecules into effective drugs. Crystal engineering offers some additional tools in this regard.


Figure imgf000073_0001TRELAGLIPTIN SUCCINATE

Form A may be prepared by crystallization from the various solvents and under the various crystallization conditions used during the polymorph screen (e.g., fast and slow evaporation, cooling of saturated solutions, slurries, and solvent/antisolvent additions). Tables B and C of Example 3 summarize the procedures by which Form A was prepared.

For example, Form A was obtained by room temperature slurry of an excess amount of Compound I in acetone, acetonitrile, dichloromethane, 1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water, ethylacetate, tetrahydrofuran, toluene, or other like solvents on a rotating wheel for approximately 5 or 7 days.

The solids were collected by vacuum filtration, and air dried in the hood. Also, Form A was precipitated from a methanol solution of Compound I by slow evaporation (SE). Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution 1H-NMR, and solid state 13C-NMR. Figure 1 shows a characteristic XRPD spectrum (CuKa, λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was crystalline. Major X-Ray diffraction lines expressed in °2Θ and their relative intensities are summarized in Table 1. Table 1. Characteristic XRPD Peaks (CuKa) of Form A

Figure imgf000018_0001 Figure imgf000019_0001

The above set of XRPD peak positions or a subset thereof can be used to identify Form A. One subset comprises peaks at about 11.31, 11.91, 12.86, 14.54, 15.81, 16.83, 17.59, 19.26, 19.52, 21.04, 22.32, 26.63, and 29.87 °2Θ. Another subset comprises peaks at about 11.31, 11.91, 19.26, 21.04, and 22.32 °2Θ; the peaks of this subset show no shoulder peaks or peak split greater than 0.2 °2Θ. Another subset comprises peaks at about 11.31, 11.91 and 22.32 °2Θ. Figure 2 is a TGA thermogram of Form A. TGA analysis showed that Form A exhibited insignificant weight loss when heated from 25 0C to 165 0C; this result is indicative that Form A was an anhydrous solid. Figure 3 shows a characteristic DSC thermogram of Form A. DSC analysis showed a single endothermic event occurred at approximately 195 0C (peak maximum). This endothermic event was confirmed by hot stage microscopy which showed the melting of Form A, which onset around 177 0C and the melting point estimated to be at approximately 184 0C.



Figure 4 (A-D) shows a characteristic FT-IR spectrum of Form A. The major bands expressed in reciprocal wavelengths (wavenumber in cm”1) are positioned at about 3815, 3736, 3675, 3460, 3402, 3141, 3098, 3068, 3049, 2953, 2934, 2854, 2760, 2625, 2536, 2481, 2266, 2225, 2176, 1990, 1890, 1699, 1657, 1638, 1626, 1609, 1586, 1553, 1517, 1492, 1478, 1450, 1419, 1409, 1380, 1351, 1327, 1289, 1271, 1236, 1206, 1180, 1158, 1115, 1087, 1085, 1064, 1037, 1027, 971, 960, 951, 926, 902, 886, 870, 831, 820, 806, 780, 760, 740, 728, 701, 685, 668, 637, 608, 594, 567, 558, and 516 cm”1 (values rounded to the nearest whole number). This unique set of IR absorption bands or a subset thereof can be used to identify Form A.

One such subset comprises absorption bands at about 3141, 3098, 3068, 3049, 2953, 2934, 2854, 2266, 2225, 1699, 1657, 1609, 1586, 1553, 1517, 1492, 1478, 1450, 1380, 1351, 1327, 1236, 1206, 1115, 1063, 902, 886, 870, 820, 780, 760, 685, 608, 594, and 516 cm 1. Another subset comprises absorption bands at about 3141, 2953, 2934, 2854, 2266, 2225, 1699, 1657, 1450, 1206, 886, 760, 685, 594, and 516 cm 1. Yet another subset comprises absorption bands at about 3141, 2953, 2934, 2266, 1699, 1657, 1450, and 1206 cm 1.


Aprepitant case study FTIR.. READING MATERIAL

Figure 5 (A-D) shows a characteristic Raman spectrum of Form A. The major Raman bands expressed in reciprocal wavelengths (wavenumber in cm”1) are positioned at about 3100, 3068, 3049, 2977, 2954, 2935, 2875, 2855, 2787, 2263, 2225, 2174, 1698, 1659, 1626, 1607, 1586, 1492, 1478, 1451, 1439, 1409, 1400, 1382, 1351, 1328, 1290, 1281, 1271, 1237, 1223, 1213, 1180, 1155, 1134, 1115, 1084, 1063, 1035, 971, 952, 926901, 868, 805, 780, 759, 740, 727, 701, 686, 669, 609, 594, 566, 558, 516, 487, 479, 433, 418, 409, 294, 274, 241, 218, 191 and 138 cm”1 (values rounded to the nearest whole number). This unique set of Raman bands or a subset thereof may be used to identify Form A.

One such subset comprises Raman bands at about 2954, 2935, 2225, 1698, 1659, and 1607 cm”1. Another subset comprises Raman bands at about 3068, 2954, 2935, 2225, 1698, 1659, 1607, 1586, 1223, 1180, 901, 780, 759, 669, and 516 cm”1. Yet another subset comprises Raman bands at about 3100, 3068, 2225, 1698, 1659, 1607, 1586, 1351, 1237, 1223, 1180, 1155, 1134, 1115, 1063, 952, 926, 901, 868, 805, 780, 759, 740, 669, 609, and 516 cm”1.

Form A was further characterized by solution 1H NMR and solid-state 13carbon NMR. The spectra are reported in Figures 6 and 7, respectively. Chemical assignments were not performed; however, the spectra are consistent with the known chemical structure of Compound I. US8084605

Figure imgf000073_0001 Example 11. Characterization of Form A Material prepared by the procedure of Example 1 was designated as Form A. The material was characterized by XRPD, TGA, DSC, hot stage microscopy, FT-IR, FT- Raman, 1H NMR, and 13C NMR. The analyses were conducted according to the procedures outlined in Section B of Example 3.

The characteristic spectra and thermograms for Form A are reported in Figures 1-7. The characterization data are summarized in Table D. Table D. Characterization Data of Form A of Compound I US8084605

Figure imgf000064_0001

Amorphous solid dispersion screening

Using the amorphous form of a drug substance offers several advantages with respect to dissolution rate and solubility of the substance. However, reduced chemical stability, increased hygroscopicity and, most important, physical instability are the major drawbacks of using the amorphous phase in the final drug product. These drawbacks can be overcome by stabilizing the amorphous phase of the API in a polymer matrix, e.q. an amorphous solid dispersion. Amorphous phases dissolve more rapidly than crystalline forms, and can significantly increase bioavailability of poorly water soluble drugs substances. However, the use of amorphous materials requires confidence that crystallization will not occur during the product lifespan. For a material that has never been obtained in a crystalline form, focus should be put on attempting to crystallize it. Crystallics has extensive experience of obtaining crystalline phases from amorphous materials.

Dispersions of a drug substance onto a polymeric matrix has received increased attention in recent years. A successful dispersion results in an amorphous solid material and will show improved dissolution rates and higher apparent solubility characteristics, as well as, sufficient resistance to chemical degradation and should be physically stable e.q. sufficient high glass transition temperature avoiding crystallization of the API.

A variety of factors contribute to the formation of a suitable Amorphous Solid Dispersion (ASD), including the nature of the polymer, the drug polymer ratio, the impact of surfactants and the solvent used in the process. Crystallics has developed high-throughput solid dispersion screening technology in order to find the optimal combination of these factors.

Example 10. Preparation of Amorphous Form US8084605

A sample of Compound I (40 mg) was dissolved in 1000 μl of water. The solution was filtered through a 0.2 μm nylon filter into a clean vial then frozen in a dry ice/acetone bath. The vials were covered with a Kimwipe then placed on a lyophilizer overnight. The resulting solids yielded Amorphous Form. 8. Amorphous Form The Amorphous Form of Compound I was prepared by lyophilization of an aqueous solution of Compound I (Example 10). The residue material was characterized by XRPD and the resulting XRPD spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo with no specific peaks present, which confirms that the material is amorphous. The material was further characterized by TGA, DSC, hot stage microscopy, and moisture sorption analysis.

TGA analysis (Figure 27) showed a 1.8% weight loss from 25 0C to 95 0C, which was likely due to loss of residual solvent.

DSC analysis (Figure 28) showed a slightly concave baseline up to an exotherm at 130 0C (recrystallization), followed by an endotherm at 194 0C, which results from the melting of Form A. Hot stage microscopy confirmed these recrystallization and melting events (micrographs not included). An approximate glass transition was observed (Figure29) at an onset temperature of 82 0


Moisture sorption/desorption data (Figure 30 and Example 25) showed a 1.0% weight loss on equilibration at 5% relative humidity. Approximately 8% of weight was gained up to 65% relative humidity. Approximately 7% of weight was lost at 75% relative humidity. This is likely due to the recrystallization of the amorphous material to a crystalline solid. A 4.4% weight gain was observed on sorption from 75% to 95% relative humidity. Approximately 4.7% weight was lost on desorption from 95% to 5% relative humidity.

The solid material remaining after the moisture sorption analysis was determined to be Form A by XRPD (Figure 31). Table H. Characterization Data of Amorphous Form US8084605

Figure imgf000068_0001

T=temperature, RH=relative humidity, MB = moisture sorption/desorption analysis Example 19: Relative Humidity Stressing Experiments

 Moisture Sorption/Desorption Study of Amorphous Form.
Mositure sorption and desorption study was conducted on a sample of Amorphous Form. The sample was prepared by lyophilolization of a solution of Compound I in water (Example 3, section A.9). The mositure sorption and desorption study was conducted according to the procedures outlined in Example 3, section B.10. The data collected is plotted in Figure 29 and summarized in Table N .Table N. Moisture Sorption/Desorption of Amorphous Form
Figure imgf000072_0001

Table B. Crystallization Experiments of Compound I from Solvents

Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001

a) FE = fast evaporation; SE = slow evaporation; RT = room temperature; SC = slow cool; CC = crash cool, MB = moisture sorption/desorption analysis b) qty = quantity; PO = preferred orientation Table C. Crystallization Experiments of Compound I in Various Solvent/Antisolvent

Figure imgf000062_0002

a precipitated by evaporation of solvent Table A. Approximate Solubilities of Compound I US8084605

Figure imgf000052_0001
Figure imgf000053_0001

a) Approximate solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.

Example 3.

Polymorph Screen Compound I as prepared by the method described in Example 1 was used as the starting material for the polymorph screen. Solvents and other reagents were of ACS or HPLC grade and were used as received. A. Sample Generation. Solids for form identification were prepared via the following methods from Compound I.

1. Fast Evaporation (FE) A solution of Compound I was prepared in test solvents. The sample was placed in the hood, uncovered, to evaporate under ambient conditions. The solids were analyzed by XRPD for form identification.

2. Slow Evaporation (SE) A solution of Compound I was prepared in test solvents. The sample was placed in the hood, covered with foil rendered with pinholes, to evaporate under ambient conditions. The solids were analyzed by XRPD for form identification.

3. Room Temperature (RT) Slurries An excess amount of Compound I was slurried in test solvent on a rotating wheel for approximately 5 or 7 days. The solids were typically collected by vacuum filtration, air dried in the hood, and analyzed by XRPD for form identification.

4. Elevated Temperature Slurries Excess Compound I was slurried in test solvents at 47 0C on a shaker block for approximately 5 days. The solids were collected by vacuum filtering, dried in the hood, and then analyzed by XRPD for form identification.

5. Slow Cooling Crystallization (SC)

A saturated or near saturated solution of Compound I was prepared at elevated temperature. The samples were filtered through warmed 0.2 μm filters into warmed vials. The heat source was turned off and the samples slowly cooled to ambient temperature. If precipitation did not occur within a day the samples were placed in the refrigerator. The samples were transferred to a freezer if precipitation did not occur within several days. The solids were collected by decanting the solvent or vacuum filtration, dried in the hood and analyzed by XRPD for form identification.

6. Crash Cooling Crystallization (CC) A saturated or near saturated solution of Compound I was prepared at elevated temperature. The samples were filtered through warmed 0.2 μm filters into warmed vials then rapidly cooled in an acetone/dry ice or ice bath. If precipitation did not occur after several minutes the samples were placed in the refrigerator or freezer. Solids were collected by decanting solvent or vacuum filtration, dried in the hood, and then analyzed by XRPD. Samples that did not precipitate under subambient conditions after several days were evaporated in the hood and analyzed by XRPD for form identification.

7. Solvent/Antisolvent Crystallization (S/AS) A solution of Compound I was prepared in test solvent. A miscible antisolvent was added with a disposable pipette. Precipitate was collected by vacuum filtration or decanting solvent. The samples were stored under subambient conditions if precipitation did not occur. If solids were not observed after several days the samples were evaporated in the hood. Collected solids were analyzed by XRPD for form identification.

8. Relative Humidity (RH) Stressing Experiments Samples of Compound I were placed uncovered in approximately 58%, 88%, and 97% relative humidity jars. The samples were stored in the jars for approximately 8 days. The solids were collected and analyzed by XRPD for form identification.

9. Lyophilization Compound I was dissolved in water in a glass vial. The solution was frozen by swirling the vial in an acetone/dry ice bath. The frozen sample was placed on the lyophilizer until all of the frozen solvent was removed. The solids were collected and analyzed by XRPD for form identification.

10. Grinding Experiments Aliquots of Compound I were ground manually with a mortar and pestle as a dry solid and a wet paste in water. The samples were ground for approximately three minutes. The solids were collected and analyzed by XRPD for form identification.

11. Dehydration Experiments Hydrated samples of Compound I were dehydrated at ambient conditions (2 days) and in an ambient temperature vacuum oven (1 day). The solids were collected and analyzed by XRPD for form identification.

12. Vapor Stress Experiments Amorphous Compound I was placed in acetone, ethanol, and water vapor chambers for up to eight days. The solids were collected and analyzed by XRPD for form identification.

STABILITY STUDY Stability studies are commonly performed for new drug entities with chemical stability and impurity formation being investigated. It is also important to monitor the physical stability under these same conditions to anticipate any form changes that may occur. As an example, many hydrates will dehydrate to a lower hydrate or anhydrous form at elevated temperatures. Anhydrous materials can also undergo form transformations to other anhydrous forms upon heating.

These types of changes can be monitored using heating studies in an oven with subsequent XRPD analysis or in-situ variable temperature XRPD can be used to look for changes. In other cases, anhydrates will convert to hydrates or the API in an amorphous solid dispersion may crystallize under elevated relative humidity (RH) conditions.

Equilibration in RH chambers with subsequent analysis by XRPD or in-situ variable RH XRPD experiments can be used to readily identify these form changes. Once the effect of temperature and RH on form changes is understood, this can be factored into other processes such as drying, formulation, storage, and packaging B. Sample Characterization. The following analytical techniques and combination thereof were used determine the physical properties of the solid phases prepared.

1. X-Ray Powder Diffraction (XRPD)

XRPD is commonly used as the initial method of analysis for form screens. For polymorph, salt, and co-crystal screens XRPD is used to determine if a new form has been produced by comparing the powder pattern to all known forms of the API and the counterion/guest. If a new form is found by XRPD, additional characterization by other methods is in order. For amorphous solid dispersion screens, XRPD is used to confirm a lack of crystallinity indicated by an amorphous halo in the powder pattern.

The halos will move depending on the concentration and interactions of the API and polymer. Computational methods have also been used with XRPD data to establish miscibility of amorphous solid dispersions X-ray powder diffraction is a front line technique in solid form screening and selection based on its ability to give a fingerprint of the solid-state structure of a pharmaceutical material. Understanding the solid forms of a pharmaceutical compound provides a road map to help direct a variety of development activities ranging from crystallization, formulation, packaging, storage, and performance.

Different screening and selection strategies are warranted in early and late development because different information is needed at the various stages. Solid form selection and formulation approaches need to be investigated together and tailored to the situation. It is important to include solid form selection and possible changes in form as part of the risk management strategy throughout the drug development process.

X-ray powder diffraction (XRPD) analyses were performed using an Inel XRG- 3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2Θ (2Θ) range of 120°. Real time data were collected using Cu-Ka radiation starting at approximately 4 °2Θ at a resolution of 0.03 °2Θ. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The pattern is displayed from 2.5 to 40 °2Θ. Samples were prepared for analysis by packing them into thin- walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for approximately 5 minutes.

Instrument calibration was performed using a silicon reference standard. Peak picking was performed using the automatic peak picking in the Shimadzu XRD-6000 Basic Process version 2.6. The files were converted to Shimadzu format before performing the peak picking analysis. Default parameters were used to select the peaks.

2. Thermogravimetric Analysis (TGA)

Thermogravimetric (TG) analyses were performed using a TA Instruments 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was first equilibrated at 25 0C, then heated under nitrogen at a rate of 10 °C/min, up to a final temperature of 350 0C. Nickel and Alumel™ were used as the calibration standards.

3. Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter 2920. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and then crimped. The sample cell was equilibrated at 25 0C and heated under a nitrogen purge at a rate of 10 °C/min, up to a final temperature of 350 0C. Indium metal was used as the calibration standard. Reported temperatures are at the transition maxima. For studies of the glass transition temperature (Tg) of the amorphous material, the sample cell was equilibrated at ambient temperature, then heated under nitrogen at a rate of 20 °C/min, up to 100 0C. The sample cell was then allowed to cool and equilibrate at -20 0C. It was again heated at a rate of 20 °C/min up to 100 0C and then cooled and equilibrated at -20 0C. The sample cell was then heated at 20 °C/min up to a final temperature of 350 0C. The Tg is reported from the onset point of the transition.

4. Hot Stage Microscopy.

Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. The samples were prepared between two cover glasses and observed using a 20χ objective with crossed polarizers and first order compensator. Each sample was visually observed as the stage was heated. Images were captured using a SPOT Insight™ color digital camera with SPOT Software v. 3.5.8. The hot stage was calibrated using USP melting point standards.

5. Thermogravimetric-Infrared (TG-IR)

Thermogravimetric infrared (TG-IR) analyses were acquired on a TA Instruments thermogravimetric (TG) analyzer model 2050 interfaced to a Magna 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. The TG instrument was operated under a flow of helium at 90 and 10 cc/min for the purge and balance, respectively. Each sample was placed in a platinum sample pan, inserted into the TG furnace, accurately weighed by the instrument, and the furnace was heated from ambient temperature to 250 0C at a rate of 20 °C/min.

The TG instrument was started first, immediately followed by the FT-IR instrument. Each IR spectrum represents 32 co-added scans collected at a spectral resolution of 4 cm“1. A background scan was collected before the beginning of the experiment. Wavelength calibration was performed using polystyrene. The TG calibration standards were nickel and Alumel™. Volatiles were identified from a search of the High Resolution Nicolet TGA Vapor Phase spectral library.

6. Fourier Transform Infrared Spectroscopy (FT-IR)

Infrared spectra were acquired on a Magna-IR 560® or 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. A diffuse reflectance accessory (the Collector™, Thermo Spectra-Tech) was used for sampling. Each spectrum represents 256 co-added scans collected at a spectral resolution of 4 cm“1. Sample preparation consisted of physically mixing the sample with KBr and placing the sample into a 13 -mm diameter cup. A background data set was acquired on a sample of KBr. A Log 1/R (R = reflectance) spectrum was acquired by taking a ratio of these two data sets against each other. Wavelength calibration was performed using polystyrene. Automatic peak picking was performed using Omnic version 7.2.

7. Fourier Transform Raman Spectroscopy (FT-Raman)

FT-Raman spectra were acquired on a Raman accessory module interfaced to a Magna 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet). This module uses an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. Approximately 0.5 W of Nd)YVO4 laser power was used to irradiate the sample. The samples were prepared for analysis by placing the material in a glass tube and positioning the tube in a gold-coated tube holder in the accessory. A total of 256 sample scans were collected from at a spectral resolution of 4 cm“1, using Happ-Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane. Automatic peak picking was performed using Omnic version 7.2.

8. Solid State Nuclear Magnetic Resonance Spectroscopy (13C-NMR)

The solid-state 13C cross polarization magic angle spinning (CP/MAS) NMR spectrum was acquired at ambient temperature on a Varian UN1TYINOVA-400 spectrometer (Larmor frequencies: 13C = 100.542 MHz, 1H = 399.799 MHz). The sample was packed into a 4 mm PENCIL type zirconia rotor and rotated at 12 kHz at the magic angle. The spectrum was acquired with phase modulated (SPINAL-64) high power 1H decoupling during the acquisition time using a 1H pulse width of 2.2 μs (90°), a ramped amplitude cross polarization contact time of 5 ms, a 30 ms acquisition time, a 10 second delay between scans, a spectral width of 45 kHz with 2700 data points, and 100 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 32768 points and an exponential line broadening factor of 10 Hz to improve the signal-to- noise ratio. The first three data points of the FID were back predicted using the VNMR linear prediction algorithm to produce a flat baseline. The chemical shifts of the spectral peaks were externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm. 9. Solution Nuclear Magnetic Resonance Spectroscopy (1H-NMR) The solution 1H NMR spectrum was acquired at ambient temperature with a

Figure imgf000058_0001

spectrometer at a 1H Larmor frequency of 399.803 MHz. The sample was dissolved in methanol. The spectrum was acquired with a 1H pulse width of 8.4 μs, a 2.50 second acquisition time, a 5 second delay between scans, a spectral width of 6400 Hz with 32000 data points, and 40 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 65536 points and an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio. The spectrum was referenced to internal tetramethylsilane (TMS) at 0.0 ppm. 10.

Moisture Sorption/Desorption Analysis Moisture sorption/desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. Sorption and desorption data were collected over a range of 5% to 95% relative humidity (RH) at 10% RH intervals under a nitrogen purge. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.0100% weight change in 5 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaCl and PVP were used as calibration standards

Does solid form matter? 

Sometimes the properties of two solid forms of a drug are quite similar. In other cases, the physical and chemical properties can vary dramatically and have great impact on pharmacokinetics, ease of manufacturing, and dosage form stability. Properties that can differ among solid forms of a substance include color, solubility, crystal shape, water sorption and desorption properties, particle size, hardness, drying characteristics, flow and filterability, compressibility, and density.

Different solid forms can have different melting points, spectral properties, and thermodynamic stability. In a drug substance, these variations in properties can lead to differences in dissolution rate, oral absorption, bioavailability, levels of gastric irritation, toxicology results, and clinical trial results. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms. Stability presents a special concern, since it’s easy to inadvertently generate the wrong form at any point in the development process.

Because energy differences between forms are usually relatively small, form interconversion is common and can occur during routine API manufacturing operations and during drug product formulation, storage, and use. The stakes are high. Encountering a new solid form during late stages of development can delay filing. A new form appearing in drug product can cause product withdrawal.  

When should a search for solid forms begin?

The key to speed in the drug development process is to do it right the first time. For solid pharmaceuticals, that means:

  • identify the optimum solid form early in drug development
  • make the same form for clinical material and commercial API
  • develop a crystallization process that assures control of solid form
  • produce a drug product with solid form stability through expiration

scientists strongly recommend that investigation of possible solid forms of a new chemical entity be carried out as early in the development process as drug supply will allow. The best approach has three stages. The first stage, more relevant to some development processes than to others, is a milligram-scale abbreviated screen on efficacious compounds prior to final IND candidate selection. This early information can be used to guide selection of salts and solid forms for scale-up and toxicology studies. The second stage is full polymorph screening and selection of optimum solid form. This stage is important to all development processes and should certainly occur before the first GMP material is produced. In the case of ionic drugs, various salts should be prepared and screened for polymorphs and hydrates. The third stage, an exhaustive screen carried out before drug launch, is an effort to find and patent all of the forms of a high-potential drug. Staging the screening in this way optimizes the balance among the factors of early knowledge of options, probability of commercial success, and judicious investment of R&D money.

Delay in understanding solid form issues results in problems like different batches of clinical material having different solid forms. Another common and preventable dilemma arises when clinical trials are carried out with one form while commercial production generates another. In this case, bridging studies are required to demonstrate to regulatory agencies that the clinicals are relevant. ICH guidelines require a search for solid forms, comparison of properties that might affect product efficacy, and, if appropriate, setting of solid form specifications.

How is solid form controlled in API manufacture? 

It is important to control solid form during API synthesis in order to demonstrate complete process control to regulatory agencies. Different solid forms can have different solubilities and can affect recovery of API. Purification efficiencies can vary due to differential exclusion of impurities. Filtration and transfer characteristics often differ between forms. Ease of drying can vary due to different abilities to bind solvent and water in the crystal lattice. A prevalent but incorrect belief is that solid form is determined primarily by choice of crystallization solvent. In fact, it is well established that parameters like temperature, supersaturation level, rate of concentration or cooling, seeding, and ripening can have an overriding effect. These variables must be controlled to ensure consistency of solid form in API.

Can solid form problems arise in drug products, too? 

The potential for solid form variation does not end at API production. Solid form issues remain through formulation, manufacture, storage, and use of drug product. It is common to observe form transformation during standard manufacturing operations like wet granulation and milling. Excipient interactions and compaction can induce form changes. Changes can occur in the final dosage form over time. Suspensions, including those in transdermal patches, are particularly vulnerable because they provide a low-energy pathway (dissolution/recrystallization) for form interconversion. Lyophile cakes are normally amorphous, but can crystallize on storage leading to difficulty in reconstitution. Even products containing drug in solution, such as filled gel caps, can be affected if the solution is or becomes supersaturated with respect to one of the possible solid forms of the drug.

How can you tell when you have a solid form problem? 

Whenever there is a specification failure in drug product or drug substance, solid form changes should be considered in the search for causes. Particularly symptomatic is failure to meet melting point or dissolution specifications. Changes in humidity, crystallization conditions, or crystallization solvent can produce unwanted forms. Solvents known to readily produce solvates include water, alcohols, chlorinated hydrocarbons, cyclic ethers, ketones, nitriles, and amides. Changes in the appearance of gel caps or cracking of tablet coatings can indicate solid form problems. Various solid-state analytical techniques can be used to identify solid form in API. Some techniques can even determine solid form of API in intact final dosage form. Among the most useful techniques for solid-state characterization are melting point, DSC, TGA, hot stage and optical microscopy, solid-state NMR, IR and Raman spectroscopy, and X-ray powder diffraction.

Is there any good news about polymorphism? 

Polymorphism presents opportunities as well as challenges. Investigation of the properties of different forms of a commercial drug can lead to new products with improved onset time, greater bioavailability, sustained release properties, or other therapeutic enhancements. New forms can bring improvements in manufacturing costs or API purity. These improvements are patentable and can provide a competitive advantage. An underutilized potential of polymorphism is to solve formulation problems that cause the abandonment of potentially useful drugs in which much investment has already been made.


Solubility is an important parameter for new molecules especially with the emergence of many poorly soluble compounds in the drug discovery and development pipeline. Polymorphic forms can exhibit solubility differences that vary within a factor of 1-5, amorphous solid dispersions show an improvement one or two orders of magnitude higher, and salts and co-crystals fall between these extremes . A comparison of solubility values of pure forms will provide important information when deciding on a solid form or dosage form. X-ray powder diffraction will allow identification of pure forms for these types of measurements.

However, form changes during solubility and dissolution experiments are also possible and need to be investigated. Solids remaining at the end of solubility and dissolution experiments should always be analyzed initially by XRPD to determine if a form transformation has occurred under these conditions. If a form change has occurred, XRPD patterns can be compared to known forms (polymorphs, hydrates, salts, free acid/base) in order to identify the solids remaining. If a pattern is obtained that does not correspond to known forms, complementary methods will be needed to determine properties such as hydration state or a change in stoichiometry as would be observed from breaking a salt and forming the free acid/base or the formation of salts in buffered solutions.


Formulators are charged with the responsibility to formulate a product which is physically and chemically stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable crystalline or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissolution rate or higher concentration are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-solubility drug.

Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable crystalline or amorphous form. Whether or not there is medical benefit, the risks associated with development of a metastable form must be mitigated by laboratory work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) analytical methodology and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.

Crystal engineering and co-crystals

Crystal engineering is generally considered to be the design and growth of crystalline molecular solids with the aim of impacting material properties. A principal tool is the hydrogen bond, which is responsible for the majority of directed intermolecular interactions in molecular solids. Co-crystals are multi-component crystals based on hydrogen bonding interactions without the transfer of hydrogen ions to form salts – this is an important feature, since Brønsted acid-base chemistry is not a requirement for the formation of a co-crystal.

Co-crystallization is a manifestation of directed self-assembly of different components. Co-crystals have been described of various organic substances over the years (33,34) and given various names, such as addition compounds (35,36) molecular complexes (37,38) and heteromolecular co-crystals (39). Regardless of naming convention, the essential meaning is that of a multi-component crystal where no covalent chemical modification of the constituents occurs as a result of the crystal formation. Pharmaceuticals co-crystals have only recently been discussed as useful materials for drug products.  

Pharmaceutical co-crystals

Pharmaceutical co-crystals can be defined as crystalline materials comprised of an active pharmaceutical ingredient (API) and one or more unique co-crystal formers, which are solids at room temperature. Co-crystals can be constructed through several types of interaction, including hydrogen bonding, p-stacking, and van der Waals forces. Solvates and hydrates of the API are not considered to be co-crystals by this definition. However, co-crystals may include one or more solvent/water molecules in the crystal lattice. An example of putative design, a construction and preparation process is shown in Figure 2 for the 5-fluororuracil:urea 1:1 co-crystal(40).

This real example neatly illustrates the opportunity and challenge that exists currently with designing pharmaceutical co-crystals. Firstly, the ‘design’ is challenging because we have no ability to predict the exact crystal structure that may result from a crystallization attempt. By analogy to the challenge of deriving protein structure from first principles, the primary sequence (chemical structure in our case) is known and elements of secondary structure (the 2-D tape construction in Figure 2) are somewhat discernible from primary information. Prediction of the actual 3-D folded conformation (tertiary structure or obtained by self-assembly) is not possible. In other words, while we currently have the ability to project which things associate in what approximate manner on the secondary level, crystal structure prediction is essentially an intractable proposition.

By extension, and just as the exact function of a protein and quantitative parameters of activity are not predictable from primary and secondary structure, the prediction of crystal properties is not possible in the absence of structural information and measurements. There is early evidence that practitioners were aware that apparent co-crystallization of drugs could lead to useful preparations (41). In fact, a ‘chemical compound’ composed of sulfathiazole and proflavin dubbed flavazole was used to treat bacterial infection during the Second World War (42).

The case of flavazole reveals insight into how two different molecules might interact in a putative co-crystal:“… flavazole is definitely a chemical compound containing equimolar proportions of sulphathiazole and proflavin base. It is believed that combination occurs through the acidic sulphonamide group (SO2NH) of the sulphathiazole and the basic centres of the proflavin. Perhaps the most realistic expression of the formula would be to place proflavin and sulphathiazole side by side with a comma between them.” (42)  In the second half of the 20th century, interest in co-crystals evolved into the directed study of intermolecular interactions in crystalline solids (43-45). The technical development of routine single-crystal structure determination led to a watershed of data, now largely accessible through the Cambridge Structural Database (CSD) (46,47).

The structural data have become useful for understanding the intermolecular interactions in co-crystals in atomic level detail (48). Using insight gained from analysis of the CSD and directed experimentation, scientists attempt design of co-crystals with specific properties, such as color or non-linear optical response, by selecting starting components with appropriate molecular properties likely to exhibit specific intermolecular interactions in a crystal (49-52).

However, even when chemically compatible functional groups are present it is not possible to accurately predict if a co-crystal, a eutectic mixture or simply a physical mixture will result from any given experiment. As a result of these complexities, attention has been directed at the identification and characterization of intermolecular packing motifs with the goal of developing principles for co-crystal materials (53).

Figure 2.  Steps involved in crystal engineering of a pharmaceutical phase, exemplified by the real example of co-crystallization of 5-fluorouracil and urea. Scientists in India have reported a rare example of synthon polymorphism in co-crystals of 4,4′-bipyridine and 4-hydroxybenzoic acid.

Graphical abstract: Synthon polymorphism and pseudopolymorphism in co-crystals. The 4,4′-bipyridine–4-hydroxybenzoic acid structural landscape

Polymorphism is defined as the ability of a material to exist in more than one form or crystal structure. It has important implications for the properties of such materials; for example in pharmaceuticals, the dissolution rate of a drug can be dependent on the polymorphic form. While this is a common phenomenon in single crystals it is much less common in co-crystals, systems where the structure has at least two distinct components. Gautam Desiraju from the Indian Institute of Science, found that when 4,4′-bipyridine and 4-hydroxybenzoic acid were dissolved together in a solvent such as methanol they would co-crystallise to form two different polymorphs. They noticed that a third form, a pseudopolymorph, was also present.


At the beginning of the 21st century, the field of crystal engineering has experienced significant development. Importantly, crystal engineering principles are now being actively considered for application to pharmaceuticals to modulate the properties of these valuable materials (54).

Because the physical properties that influence the performance of pharmaceutical solids are reasonably well appreciated, there is a unique opportunity to apply crystal engineering techniques and the appropriate follow-up studies to solve real world problems, such as poor physical and chemical stability or inadequate dissolution for appropriate biopharmaceutical performance of an oral drug. As structures and series of pharmaceutical co-crystals have begun to appear, we again find that properties cannot be predicted from the structures.  Nevertheless, occasional trends have been suggested.

For example, insoluble drug compounds co-crystallized with highly water soluble complements tend to achieve kinetic solubilities in aqueous media several times greater than the pure form (55,56).

There are also more possible phases for each given active compound to consider, thus there will arguably be a greater opportunities for property enhancement. In terms of stability enhancement and solubilization, the example of the series of itraconazole co-crystals with pharmaceutically acceptable 1,4-diacids (55) suggests a strategy alternative to amorphous drug formulation. The co-crystal options presented retain the stability inherent in a crystalline state, while allowing for solubilization that significantly exceeds that of crystalline itraconazole base and rivals the performance of the engineered amorphous bead formulation (Sporanox®).

Where are we now? From recent literature it appears that knowledge gained over the past century and increasingly sophisticated screening techniques developed within the last decade are paving the way towards design of co-crystals with potentially improved pharmaceutical properties (55-58) In terms of the application to pharmaceutical systems, the field of crystal engineering is developing the retro-synthetic understanding of crystal structure using reasoning that is analogous to that applied by organic chemists.  For example, the retro-synthetic approach in covalent synthesis operates on the level of a single molecule, while the analogous effort in crystal engineering focuses on the “supermolecule”:


The assemblies that define the crystalline arrangement of the molecules as they self-organize into the solid-state. The parallels between the development of crystal engineering and synthetic organic chemistry run still deeper. Methodologies for carrying out these crystallizations are being developed alongside the development of new robust motifs (6,53,55,57,60). The importance of the solubility and dissolution relationships of the components of a putative co-crystal is becoming a matter of significant investigation (56,60). The same can be said for the roles of additives in templating novel forms.

Mechanical milling of materials has also been documented as a means to make co-crystals, and a recent example of polymorphic forms of caffeine:glutaric acid illustrates the opportunities of this type of processing to influence crystal form (61). With an increase in the understanding of the modes of self-assembly, one can start to address the design aspect towards making pharmaceutical co-crystals.

There remain several limitations to the application of what is currently known to the design of useful materials. As mentioned earlier, it remains intractable to reliably predict crystal structure.  Multi-component crystals are well out of reach for prediction due in part to complex energetic landscapes, lack of appropriate charge density models and a large number of degrees of freedom, making computation unfeasible. Moreover, there is only a qualitative understanding of the interplay between intermolecular interactions and materials performance, especially for properties relevant to pharmaceuticals such as solubility, dissolution profile, hygroscopicity and melting point.

But the saving grace of the co-crystal approach comes in two guises: Complementarity and diversity. On the topic of complementarity, it is possible, by way of CSD database mining for instance, to identify trends of hetero-synthon occurrence in model systems. As for the diversity aspect, the space of possible co-crystal formers is large, limited only by pharmaceutical acceptability. Coupled with parameters such as stoichiometry variation and increase in the number of components (binary systems can be expanded into ternary ones, etc.), the opportunities appear vast.




Novel Challenges in Crystal Engineering: Polymorphs and New…/novel-challenges-in-crystal-engineering-polymNovel Challenges in Crystal Engineering: Polymorphs and New Crystal Forms of ActivePharmaceutical Ingredients

Where are we going?  At this point, we have only just scratched the surface of materials science-driven pharmaceutical product design. In the 21st century, practitioners of pharmaceutical chemistry need to enumerate and exploit the opportunities of crystal form design that nature affords us, and thus gain increasing ability to design the materials we need from the molecules that we seek to convert into pharmaceuticals.

Learning will be facilitated by advances in crystallization automation (6,62), microscopy-spectroscopy techniques (Raman and IR microscopy) and new techniques such as terahertz spectroscopy and AFM, along with increasingly sophisticated X-ray diffraction lab instrumentation. In addition, further enhancements in the data mining tools associated with the CSD operating on an ever increasing number of high-quality crystal structures will undoubtedly lead to new knowledge and principles of interaction.

The challenge placed before pharmaceutical scientists, now and in the future, is the following: (i) to understand the requirement of a particular compound in terms of materials structure and properties, and (ii) to creatively integrate crystal engineering within the limits of pharmaceutical acceptability of components to obtain new forms of active ingredients with desirable properties for formulation and delivery. It should become the collective mantra of medicinal chemists, process engineers and pharmaceutical scientists to “design and make the material we need.” This mantra can form the common aspiration for an industry that is in significant need of innovation and productivity enhancement.

Applications and Advantages


  • Drug companies can use this technology to protect themselves against others generating and patenting polymorphs


  • Having more than one solid form of a drug allows optimization of drug dissolution behavior and shelf life


In order for a new drug to enter the market, pharmaceutical companies must invest for many years in very expensive clinical trials and a lengthy regulatory approval process.Market protection plays therefore a major role in the growth of the pharmaceutical industry and Intellectual Property (IP) laws are intended to give the investors an opportunity to recover their costs. Patent filing is one way of efficiently protecting various aspects of an innovative drug.
The duration of the new drug’s market protection is, however, limited in time and once the original drug is no longer protected, legal copies (generic medicines) can be developed and marketed by competitors at more accessible prices, since the expensive basic research, as well as pre-clinical and clinical trials (at least for small molecules) are no longer necessary. Generic medicines are either identical copies of the original drug or so-called bioequivalent versions of it.
Bioequivalent means that they behave as the original drug when administered to patients. For a generic drug to be a bioequivalent its Active Pharmaceutical Ingredient (API) does not need to be the same solid form as in the original drug. A different polymorph or a pseudo-polymorph (i.e. solvate, hydrate) of the API and different excipients are acceptable variants, as long as the final generic drug product behaves as the original one.  
Solid Forms Screening
Screening of solid forms, in particular polymorphs of APIs, is therefore an essential part of pharmaceutical development and lifecycle management, not only for scientific and regulatory reasons, but also because of the key role that pharmaceutical solid forms play in the area of IP, for innovators as well as for generic companies. The knowledge generated by conducting solid form screening, in fact, can provide an innovator company the opportunity to build a strong patent portfolio around different solid forms and therefore a way to maximize returns from drug development.
This allows innovator companies to gain several years of additional protection for their product after the expiry of the basic molecule patent, since various pharmaceutical solid forms are individually patentable. In the US, for instance, innovator companies are required to identify, in the so-calledOrange Book, their patents covering different solid forms performing the same as the product described in the corresponding NDA. In return, they can benefit from a 30-months stay over a generic company which would eventually file an ANDA with aParagraph IV Certification for any of these listed patents.
Thus, by patenting a maximum number of possible solid forms, even if these are not further developed and used, innovator companies can more efficiently protect their own products. Such patents must obviously meet the same patentability criteria as other inventions. Conversely, a generic company can launch its own product if, after the basic molecule patent has expired, it discovers a new solid form, i.e. a form with no IP protection and suitable characteristics for product development.
In both cases, a very sensitive tool as SR-XRPD can play a key role in helping the detection and characterization of a maximum number of polymorphs.
 Accurate and direct characterization of the API polymorphic forms and detection of trace amounts has proven to be of paramount importance (e.g. Paxil®, Cefdinir) whereas poorly conducted screens and unsuccessful patenting strategies, on the other hand, can have significant negative commercial consequences (e.g. Ritonavir).
Interestingly, in the US the first ANDA approved by FDA with paragraph IV certification is entitled to 180-days marketing exclusivity. Initially granted only when theANDA applicant having filed Paragraph IV Certification could prevail in the litigation with the originator, the new FDA guidance suppresses the “successul defence”requirement and the 180-days exclusivity is decided on a case-by-case basis and can therefore be granted even if the case is settled.
While there has been much discussion by policymakers and stakeholders about the effects of “secondary patents” on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.
It is seen the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. It is seen that  distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims (“independent” secondary patents).
It is seen  that secondary claims are common in the pharmaceutical industry. It is seen that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). evidence that late-filed independent secondary patents are more common for higher sales drugs
Polymorph quantification. REF 79
The ability to detect and quantify polymorphism of pharmaceuticals is critically important in ensuring that the formulated product delivers the desired therapeutic properties because different polymorphic forms of a drug exhibit different solubilities, stabilities and bioavailabilities. The purpose of this study is to develop an effective method for quantitative analysis of a small amount of one polymorph within a binary polymorphic mixture. Sulfamerazine (SMZ), an antibacterial drug, was chosen as the model compound. The effectiveness and accuracy of powder X-ray diffraction (PXRD), Raman microscopy and differential scanning calorimetry (DSC) for the quantification of SMZ polymorphs were studied and compared.
Low heating rate in DSC allowed complete transformation from Form I to Form II to take place, resulting in a highly linear calibration curve. Our results showed that DSC and PXRD are capable in providing accurate measurement of polymorphic content in the SMZ binary mixtures while Raman is the least accurate technique for the system studied.
DSC provides a rapid and accurate method for offline quantification of SMZ polymorphs, and PXRD provides a non-destructive, non-contact analysis.A novel method of detecting very low levels of different polymorphs using high-resolution X-ray powder diffraction with a synchrotron light source has been developed by Zach-Zambon Chemicals of Italy. Key to the project has been development of software to enable appropriate data presentation.The issue of polymorphism in pharmaceuticals has attracted increasing attention over the past 20 years and is something to which development scientists and the regulatory authorities pay considerable attention.



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63……..POLYMORPHISM AND PATENTS 64…Aprepitant case study FTIR.. READING MATERIAL 65…..READ………….An Overview of Solid Form Screening During Drug Development, 66…..CRYSTALLIZATION..

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  1. H. Brittain. Methods for the characterization of polymorphs and solvates. In H. G. Brittain (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999, pp. 227-278.
  2. L. X. Yu and G. L. Amidon GL. Analytical Solutions to Mass Transfer. In: G. L. Amidon, P. I. Lee, and E. M. Topp (eds.) Transport Processes in Pharmaceutical Systems. Marcel Dekker, Inc., 1999, p. 23-54.
  3. G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413-420 (1995).
  4. L. X. Yu, G. L. Amidon, J. E. Polli, H. Zhao, M. Mehta, D. P. Conner, V. P. Shah, L. J. Lesko, M.-L. Chen, V. H. L. Lee, and A. S. Hussain. Biopharmaceutics Classification System: The scientific basis for biowaiver extension. Pharm. Res. 19:921-925 (2002).
  5. S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-State Chemistry of Drugs. 2nd Edition, SSCI, Inc., West Lafayette, Indiana, pp. 259-366.
  6. H. G. Brittain and E. F. Fiese. Effect of pharmaceutical processing on drug polymorphs and solvates. In H. G. Brittain (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999, pp. 331-362.


72 API………….POLYMORPHISM pharmaceutical ingredients (APIs).

73 polymorphs and co-crystals – ICDD  POWER POINT PRESENTATION

74Thermodynamic stability and transformation of pharmaceutical×0581.pdf


76  High-throughput crystallization: polymorphs, salts, co-crystalsand solvates of pharmaceutical solids

77 Crystalline Solid – University of Utah College of Pharmacy‎Form – a term encompassing all solids – polymorphs, solvates, amorphous  inPolymorphism in Pharmaceutical Solids


78..related to xrd

  1. Bish, DL and Post, JE, editors. 1989. Modern Powder Diffraction. Reviews in Mineralogy, Vol. 20. Mineralogical Society of America
  2. Cullity, B. D. 1978. Elements of X-ray diffraction. 2nd ed. Addison-Wesley, Reading, Mass
  3. I. Ivanisevic, R. B. McClurg and P. J. Schields: Uses of X-Ray Powder Diffraction in the Pharmaceutical Industry, Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development and Manufacturing, Ed. by Shayne C. Gad., p. 1-42 (2010).
  4. S. R. Byrn, S. Bates and I. Ivanisevic: Regulatory Aspects of X-ray Powder Diffraction, Part 1, American Pharmaceutical Review, p.55-59 (2005)
  5. D. Beckers: The power of X-ray analysis, Pharmaceutical Technology Europe (2010), p.29,30.
  6. M. Sakata, S. Aoyagi, T. Ogura & E. Nishibori (2007): Advanced Structural Analyses by Third Generation Synchrotron Radiation Powder Diffraction, AIP Conference Proceedings, Vol. 879, pp. 1829-1832 (2007).
  7. Bergamaschi, A.; Cervellino, A.; Dinapoli, R.; Gozzo, F.; Henrich, B.; Johnson, I.; Kraft, P.; Mozzanica, A.; Schmitt, B.; Shi, X.: The MYTHEN detector for X-ray powder diffraction experiments at the Swiss Light Source. J. Synchrotron Rad. 17 (2010) 653–668.
  8. R.B. Von Dreele, P.W. Stephens, G.D. Smith, and R.H. Blessing: The First Protein Crystal Structure Determined from X-ray Powder Diffraction Data: a Variant of T3R3 Human Insulin Zinc Complex Produced by Grinding,Acta Cryst. D 56, 1549-53 (2000).
  9. Margiolaki, I., Wright, J. P., Fitch, A. N., Fox, G. C. & Von Dreele, R. B.: Synchrotron X-ray powder diffraction study of hexagonal turkey egg-white lysozyme, Acta Cryst. D61, 423–432 (2005). See also: Margiolaki, I. & Wright, J. P.: Powder crystallography on macromolecules, Acta Cryst. A64, 169–180 (2008).
  10. Fundamentals of Crystallography,C. Giacovazzo Ed., International Union of Crystallography, Oxford Science Publications, Third Edition (2011).
  11. The basics of Crystallography and Diffraction (Third edition, 2010), Christopher Hammond, IUCr, Oxford Science Publications; ISBN 978-0-19-954645-9. See also: X-Ray Structure Determination, A practical Guide, George H. Stout and Lyle H. Jensen, Wiley Interscience.
  12. Bruni G, Gozzo F, Capsoni D, Bini M, Macchi P, Simoncic P, Berbenni V., Milanese C., Girella A., Ferrari S. and Marini A., Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs, J. Pharm. Sciences 100(6), 2321 (2011).
  13. Brunelli, M., Wright, J. P., Vaughan, G. B. M., Mora, A. J. & Fitch, A. N.: Solving Larger Molecular Crystal Structures from Powder Diffraction Data by Exploiting Anisotropic Thermal Expansion. Angew. Chem. (2003) 115, 2075–2078.
  14. T. Wessels, Ch. Baerlocher and L.B. McCusker: Single-crystal-like diffraction data from polycrystalline materials, Science (1999), 284, 477-479.
  15. Shankland, K., David, W. I. F., Csoka, T. & McBride, L.: Structure solution of Ibuprofen from powder diffraction data by the application of a genetic algorithm combined with prior conformational analysis,  Intl. J. Pharmaceut. (1998) 165, 117–126.
  16. A. Altomare, C. Cuocci, C. Giacovazzo, A. Moliterni and R. Rizzi: The dual-space resolution bias correction algorithm: applications to powder data, J. Appl. Cryst. (2010). 43, 798-804.
  17. G.Oszlanyi and A. Suto: The charge flipping algorithm, Acta Cryst. (2008). A64, 123–134 and references herein.
  18. Boccaleri, E., Carniato, F., Croce, G., Viterbo, D., van Beek, W., Emerich H. and Milanesio, M.,In-situ simultaneous Raman/high-resolution X-ray powder diffraction study of transformations occurring in materials at non-ambient conditions, J. Appl. Cryst., 2007, 40, 684-693.
  19. Scarlett N.V.Y. and Madsen I. C., Quantification of phases with partial or no known crystal structures, Powder Diffraction (2006) 21, 278-284
  20. Giannini C., Guagliardi A. and Millini R., Quantitative phase analysis by combining the Rietveld and the whole-pattern decomposition methods, J. Appl. Cryst., 2002, 35, 481-490.
  21. Scardi, P.; Leoni, M.: Line profile analysis: pattern modeling versus profile fitting, J. Appl. Cryst. 39 (2006) 24–31. Scardi, P.; Leoni, M.: Whole Powder Pattern Modelling, Acta Crystall. A58 (2002) 190–200
  22. Local structure from total scattering and atomic pair distribution function (PDF) analysis, In Powder diffraction: theory and practice, (Royal Society of Chemistry, London England, 2008), Robert E. Dinnebier and Simon J. L. Billinge, Eds., pp. 464 – 493.
  23. Neder R. B. And Korsunskiy V. I., Structure of nanoparticles from powder diffraction data using the pair distribution function, 2005 J. Phys.: Condens. Matter 17 S125
  24. A. Cervellino, C. Giannini, A. Guagliardi, Determination of nanoparticle, size distribution and lattice parameter from x-ray data for monoatomic materials with f.c.c. cubic unit cell, J. Appl. Cryst. 36, 1148-1158 (2003).
  25. P.W. Stephens, D.E. Cox, and A.N. Fitch, Synchrotron Radiation Powder Diffraction in Structure Determination by Powder Diffraction, pp. 49-87, edited by W.I.F. David, K. Shankland, L.B. McCusker, and C. Baerlocher, (Oxford University Press, 2002)
  26. Joel Bernstein: Polymorphism in Molecular Crystals, IUCr Monographs on Crystallography (2002), Oxford Science Publications.
  27. Polymorphism in Pharmaceutical Solids, Ed. By Harry G. Brittain, Drugs and The Pharmaceutical Sciences, Vol. 192
  28. Tremayne, M.: The impact of powder diffraction on the structural study of organic materials., Philosophical Transactions of the Royal Society of London Series A: Chemistry and Life Sciences Triennial Issue, 362: 2691 (2004).
  29. Law D, Schmitt EA, Marsh KC, Everitt EA,Wang W, Fort JJ, Krill SL, Qiu Y. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J. Pharm. Sci. 2004; 93 (3): 563–567.
  30. Bruni G., Berbenni V., Milanese C., Girella A., Cardini A., Lanfranconi S. and Marini A.,Determination of the nateglinide polymorphic purity through DSC, J. Pharm. and Biomed. Anal. 54 (2011) 1196-1199.
  31. Aaltonen J., Alleso M., Mirza S., Koradia V., Gordon K.C and Rantanen J., Solid form screening – A review. European Journal of Pharmaceutics and Biopharmaceutics 71 (2009), 23-37.
  32. Srivastava D., The Food and Drug Administration and Patent Law at a Crossroads: The Listing of Polymorph Patents as a Barrier to Generic Drug Entry. Food and Drug Law Journal, Vol. 59, No.2 (2004), 339-354.
  33. Grabowski H. G., Kyle M., Mortimer R., Long G. & Kirson N., Evolving Brand-name And Generic Drug Competition May Warrant A Revision Of The Hatch-Waxman Act. Health Affairs, 30, no.11 (2011):2157-2166.
  34. Rakowski W. A and Mazzochi D. M., The case of disappearing polymorph: ‘Inherent anticipation’ and the impact of Smithkline Beecham Corp. v Apotex Corp. (Paxil®) on patent validity and infringement by inevitable conversion’. Journal of Generic Medicine, Vol.1, No.2 (2006):131-139.
  35. Cabri W., Ghetti P., Pozzi G. and Alpegiani M., Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study. Organic Process Research & Development 2007, 11, 64-72.
  36. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J., Ritonavir: an extraordinary example of conformational polymorphism, Pharm Res. 2001 Jun;18(6):859-66.


79………..related to estimation

  1. McCrone, W.C. in Physics and Chemistry of the Organic Solid State, Vol. 2, (Eds.: D. Fox, M.M. Labes, A. Weissberger), Interscience, New York, 1965, pp. 725-767.
  2. Bernstein, J., Davey, R.L., and Henck, JO, Concomitant Polymorphism, Angew.Chem.Int. Ed. 1999,38, 3440-3461.
  3. Polymorphism in Pharmaceutical Solids, Second Edition (Drugs and the Pharmaceutical Sciences) Harry G. Brittain (Editor) Informa HealthCare; 2nd edition (July 27, 2009)
  4. Otsuka, M., Kato, F. and Matsuda, Y., Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional powder X-ray diffractometry, Analyst, 2001, 126, 1578 – 1582.
  5. Patel, A.D., Luner, P. E. and Kemper, M. S., Low-level Determination of Polymorph composition in Physical Mixtures by Near-Infrared Reflectance Spectroscopy, J Pharm Sci 2001, 90, 360-370.
  6. Agatonovic-Kustrin S, Wu V, Rades, T, Saville, D, Tucker, I G, Powder diffractometric assay of two polymorphic forms of ranitidine hydrochloride Int J Pharm 1999, 184, 107.
  7. Hurst, V.J., Schroeder, P.A., and Styron, R.W. Accurate quantification of quartz and other phases by powder X-ray diffractometry. Analytica Chimica. Acta, 1997, 337, 233-252
  8. Campbell Roberts, S.N., Williams A.C., Grimsey, I.M., and Booth S.W., Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry—exploring preferred orientation effects J. Pharm. Biomed. Anal., 2002, 28, 1149-1159.


PART 1………..

PART 2 ……

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