Pharmaceutical API Polymorphs… case study of Trelagliptin
CASE STUDY WITH..Compound I having the formula
WO2008067465A1 OR US8084605 IS THE PATENT USED AND WITH FORM “A” AND AMORPHOUS FORM
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, http://www.icdd.com/ppxrd/10/presentations/PPXRD-10_Ann_Newman.pdf
ANN NEWMAN
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
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.
POLYMORPHISM AND PATENTS http://www.collegio.unibo.it/uploads/ideas/joelbernstein.pdf A MUST CLICK FOR PHARMA CHEMISTS
READ………..High-throughput crystallization: polymorphs, salts, co-crystalsand solvates of pharmaceutical solidshttp://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.85.5397&rep=rep1&type=pdf
Definitions
“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.
CASE STUDY FORM A ONLY US8084605
TRELAGLIPTIN 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
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.
US8084605
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 http://alpha.chem.umb.edu/chemistry/ch361/spring%2005/ftir%20polymorph.pdf
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
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
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
C.
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
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
Table B. Crystallization Experiments of Compound I from Solvents
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
a precipitated by evaporation of solvent Table A. Approximate Solubilities of Compound I US8084605
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