Pharmaceutical API Polymorphs... Case study of Trelagliptin Succinate

Case study with Compound I having the formula

Trelagliptin succinate

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

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

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.

FORMULATION

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.

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.

PROSPECTS FOR CRYSTAL ENGINEERING AND PHARMACEUTICAL CO-CRYSTALS

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”:

piracetam

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.

THE FUTURE OF CRYSTAL ENGINEERING IN PHARMACEUTICAL SCIENCE

READ

Novel Challenges in Crystal Engineering: Polymorphs and New ...

www.intechopen.com/.../novel-challenges-in-crystal-engineering-polym... Novel 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

Applications

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

patenting polymorphs

Advantages

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

shelf life

IP AND POLYMORPHS

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

SEE A SLIDESHARE PRESENTATION

http://www.slideshare.net/reychemist/polymorph-quant

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.

http://www.scientificupdate.co.uk/blog/item/polymorph-detection-and-quantification-a-novel-

method.html

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