1
`
`1 R
`
`elevance of Solid-state Properties
`for Pharmaceutical Products
`
`Rolf Hilfiker, Fritz Blatter, and Markus von Raumer
`
`1.1
`Introduction
`
`Many organic and inorganic compounds can exist in different solid forms [1–6].
`They can be in the amorphous (Chapter 10), i.e., disordered, or in the crystal-
`line, i.e., ordered, state. According to McCrone’s definition [2], “The polymorph-
`ism of any element or compound is its ability to crystallize as more than one
`distinct crystal species”, we will call different crystal arrangements of the same
`chemical composition polymorphs. Other authors use the term “polymorph”
`more broadly, including both the amorphous state and solvates (Chapter 15).
`Since different inter- and intramolecular interactions such as van der Waals in-
`teractions and hydrogen bonds will be present in different crystal structures, dif-
`ferent polymorphs will have different free energies and therefore different phys-
`ical properties such as solubility, chemical stability, melting point, density, etc.
`(Chapter 2). Also of practical importance are solvates (Chapter 8), sometimes
`called pseudopolymorphs, where solvent molecules are incorporated in the crys-
`tal lattice in a stoichiometric or non-stoichiometric [6, 7] way. Hydrates (Chapter
`9), where the solvent is water, are of particular interest. If non-volatile molecules
`play the same role, the solids are called co-crystals. Solvates and co-crystals can
`also exist as different polymorphs, of course.
`In addition to the crystalline, amorphous and liquid states, condensed matter
`can exist in various mesophases. These mesophases are characterized by exhibit-
`ing partial order between that of a crystalline and an amorphous state [8, 9].
`Several drug substances form liquid crystalline phases, which can be either ther-
`motropic, where liquid crystal formation is induced by temperature, or lyotropic,
`where the transition is solvent induced [10–12].
`Polymorphism is very common in connection with drug substances, which
`are mostly (about 90%) small organic molecules with molecular weights below
`600 g mol–1 [13, 14]. Literature values concerning the prevalence of true poly-
`morphs range from 32% [15] to 51% [16, 17] of small organic molecules. Ac-
`cording to the same references, 56 and 87%, respectively, have more than one
`
`Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker
`Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`ISBN: 3-527-31146-7
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`2
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
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`solid form if solvates are included. When a compound is acidic or basic, it is of-
`ten possible to create a salt (Chapter 12) with a suitable base or acid, and such
`a salt can in turn often be crystallized. Such crystalline salts may also exist as
`various polymorphs or solvates. Obviously, solvates, co-crystals and salts will
`have different properties from the polymorphs of the active molecule. Since
`salts generally have higher water solubility and bioavailability than the corre-
`sponding uncharged molecule, they are popular choices for drug substances.
`About half of all active molecules are marketed as salts [14, 18]. Polymorphs,
`solvates, salts, and co-crystals are schematically depicted in Fig. 1.1. We will use
`the term “drug substance” for the therapeutic moiety, which may be a solvate,
`salt or a co-crystal, while the single, uncharged molecule will be called the “ac-
`tive molecule”.
`Most drug products (formulated drug substances) are administered as oral
`dosage forms, and by far the most popular oral dosage forms are tablets and
`other solid forms such as capsules. Drugs for parenteral application are also of-
`ten stored as solids (mainly as lyophilized products) and dissolved just prior to
`use since in general the chemical stability of a molecule in the solid form is
`much higher than in solution. Drugs administered by inhalation have become
`increasingly popular, and dry powder inhalers are now commonly in use. Evi-
`dently, therefore, both the solid form of the drug substance and the selected ex-
`cipients have a strong impact on the properties of the formulated drug. Even if
`the envisaged market form of the drug is a solution, information about the sol-
`id-state properties of the drug substance may still be necessary [19]. If different
`forms have significantly different solubilities, it may be possible to unintention-
`ally create a supersaturated solution with respect to the least soluble form by
`creating a concentrated solution of a metastable form. Also, the drug substance
`will in most cases be handled as a solid in some stages of the manufacturing
`process, and its handling and stability properties may depend critically on the
`solid form.
`
`Fig. 1.1 Schematic depiction of various types of solid forms.
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`1.1 Introduction
`
`3
`
`In fact, the whole existence of a drug is affected by the properties of the solid
`form, and the final goal of solid form development is to find and select the sol-
`id with the optimal characteristics for the intended use.
`Initially, when the drug substance is first produced, one has to be certain that
`the desired solid form is obtained in a consistent, pure and reproducible man-
`ner. Subsequently, when it is formulated to obtain the drug product, one has to
`make sure that no undesired transitions occur (Chapter 13). For this phase, a
`profound knowledge of potential solvate formation is especially useful. It is
`highly advisable to avoid using solvents that can form solvates with the drug
`substance in the formulation process. Otherwise, such solvates might be gener-
`ated during formulation and subsequently desolvated in a final drying step. In
`such a situation the final polymorph would probably differ from the initial one
`– an undesirable effect in most cases. Similarly, the energy–temperature dia-
`gram (Chapter 2) of the polymorphs and the kinetics of the change from one
`polymorph into another should be known so that one can be sure that tempera-
`ture variations during the formulation process will not lead to an unacceptable
`degree of change in the solid form.
`In the next step, when the drug substance or drug product is stored during
`its shelf-life, it is imperative that the solid form does not transform over time.
`Otherwise, important properties of the drug might change drastically. Stability
`properties have to be evaluated with respect to ambient conditions, storage, and
`packaging. Thermodynamic stability depends on the environment. A solvate, for
`example, represents a metastable form under ambient conditions but is likely to
`be the most stable form in its solvent. Thermodynamically, any metastable form
`will eventually transform into a more stable form. The kinetics under which
`this transformation occurs, however, are polymorph specific. Therefore, the exis-
`tence of a more stable polymorph does not necessarily imply that a metastable
`polymorph cannot be developed.
`In the final step, when the patient takes the drug, the solubility and dissolu-
`tion rate of the drug substance will be influenced by its solid form. This will af-
`fect the bioavailability if solubility is a rate-limiting step, i.e., if the drug belongs
`to class 2 or 4 of the biopharmaceutics classification system (BCS) [20]. Because
`a change of solid form may render a drug ineffective or toxic, regulatory autho-
`rities demand elucidation and control of solid-state behavior (Chapter 15).
`Finally, thorough, experimentally obtained knowledge of the solid-state behav-
`ior also has the advantages that a good patent situation for a drug substance
`can be obtained and that valuable intellectual property can be generated (Chap-
`ter 14). Although in hindsight everything may appear to be easy and straightfor-
`ward, crystalline molecular solid-state forms are non-obvious, novel and require
`inventiveness. For instance, typically, many attempts to crystallize an amor-
`phous drug substance fail until, suddenly, a stable crystalline form is obtained.
`Once seed crystals are available, the crystallization becomes the simple last step
`of a production process.
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`4
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
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`1.2
`Drug Discovery and Development
`
`Typically, it takes eight to twelve years, or sometimes even longer, for a mole-
`cule with biological activity to progress from its first synthesis to market intro-
`duction as an efficacious, formulated drug [21]. This process is normally divided
`into two main phases: (a) research or discovery and (b) development [22]. In the
`research phase, the appropriate target for a particular disease model is identified
`and validated, and candidate molecules are synthesized or chosen from libraries.
`They are primarily tested with respect to binding affinity to the target or, if pos-
`sible, directly for their potential to alter a target’s activity. Sometimes other pa-
`rameters, such as selectivity, are also considered. Promising candidates are
`usually termed “hits”. As a rule at this stage, limited attention is paid to the
`possibility to formulate a drug for a certain administration route. Often, from a
`drug delivery aspect, simple vehicles like DMSO solutions are used. As a result,
`the activity of especially poorly water-soluble drugs may not be identified at all
`because they precipitate under the used in vitro conditions [23]. In a medicinal
`chemistry program the “hits” are then modified to improve physicochemical pa-
`rameters such as solubility and partition coefficient. This is the first time that
`solid-state properties come into play. When solubility is evaluated, it is critical to
`know whether the solubility of an amorphous or crystalline substance was mea-
`sured. Permeation measurements are performed using, e.g., Caco-2 [24], PAM-
`PA [25] or MDCK [26] assays, and dose–response studies are conducted in in vi-
`tro models. Selectivity is assessed in counter screens. At the same time, prelim-
`inary safety studies are carried out, and IP opportunities are assessed. Struc-
`ture–activity relationship (SAR) considerations play a large role at this stage.
`Molecules that show promise in all important aspects are called “leads”. Often
`several series of leads are identified and are then further optimized and scruti-
`nized in more sophisticated models, including early metabolic and in vivo stud-
`ies. Both pharmacokinetics (PK, the quantitative relationship between the admi-
`nistered dose and the observed concentration of the drug and its metabolites in
`the body, i.e., plasma and/or tissue) and pharmacodynamics (PD, the quantita-
`tive relationship between the drug concentration in plasma and/or tissue and
`the magnitude of the observed pharmacological effect) are studied in animal
`models to predict bioavailability and dose in humans. Simultaneously with char-
`acterization of the drug substance, a proper dosage form needs to be designed,
`enabling the drug substance to exert its maximum effect. For freely water-solu-
`ble drugs this is less critical than for poorly water-soluble drugs, which without
`the aid of an adequate dosage form cannot be properly investigated in the re-
`search stage. In the discovery phase, high-throughput methods play an increas-
`ingly important role in many aspects, such as target identification, synthesis of
`potential candidate molecules, and screening of candidate molecules. Consider-
`ing that only about 1 out of 10 000 synthesized molecules will reach the market
`[21], high-throughput approaches are a necessity. The optimal molecule arising
`from these assessments is then promoted to the next stage, i.e., development.
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`1.2 Drug Discovery and Development
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`5
`
`Fig. 1.2 Drug development process with a description of respective phases,
`approximate number of test persons, timelines and attrition rates. These
`numbers are a rough guideline only and can differ significantly according
`to the specific indication, the characteristics of the drug substance, etc.
`
`The development process of a pharmaceutical product is depicted in Fig. 1.2. It
`consists of a non-clinical and a clinical phase. While drug companies’ approaches
`to the non-clinical phase can differ somewhat, the clinical phase is treated very
`similarly due to regulatory requirements. In the non-clinical phase enough data
`is gathered to compile an Investigational New Drug Application (IND) in the
`US or a Clinical Trial Application (CTA) in the European Union, which is the pre-
`requisite for the first use of the substance in humans. For obvious reasons, partic-
`ular emphasis is placed on toxicology studies during this phase, including assess-
`ment of toxicity by single-dose and repeated-dose administration and evaluation of
`carcinogenicity, mutagenicity and reproductive toxicity. An absolute necessity at
`this stage is that the drug is maximally bioavailable, resulting in sufficient expo-
`sure of the animals to the drug to obtain an adequate assessment of its toxicity
`profile. Whenever possible, the need for animal studies is reduced by using,
`e.g., human cell in vitro tests. The non-clinical development phase lasts between
`one and two years, and the attrition rate is ca. 50% (Fig. 1.2). At the end of the
`non-clinical phase, the decision has to be made whether the neutral molecule, a
`salt, or a co-crystal will be developed. If a salt form or co-crystal is chosen, it
`has to be clear which salt (Section 1.4.1) or co-crystal is optimal. In the clinical
`phases the product is first tested on healthy volunteers and then on small and
`large patient populations. For certain disease indications, like oncology, Phase I
`studies are performed directly on patients. Approximate population sizes are given
`in Fig. 1.2. One has to bear in mind, however, that these numbers depend signif-
`icantly on the indication the drug is intended to treat. Attrition rates during the
`clinical phases are between 80 and 90%. During the clinical phases, analytical,
`process and dosage-form development continues in parallel with long-term toxi-
`cology studies. Of course, solid-state properties continue to play a crucial role dur-
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`6
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
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`ing both chemical development of the drug substance and pharmaceutical devel-
`opment of the dosage form.
`
`1.3
`Bioavailability of Solids
`
`An issue that has to be addressed for every drug product, and which is closely
`related to its solid-state properties, is whether its solubility and dissolution rate
`are sufficiently high. This leads to the question of what the minimal acceptable
`solubility and dissolution rates are.
`Bioavailability essentially depends on three factors: solubility, permeability
`and dose [27], and the question of minimal acceptable solubility can only be an-
`swered if the other two factors are known. According to the BCS a drug sub-
`stance is considered highly soluble when the highest strength dosage is soluble
`in 250 mL of aqueous media over the pH range 1.0–7.5 [28].
`A valuable concept for estimating what the minimum solubility of a drug sub-
`stance for development purposes should be uses the maximum absorbable dose
`(MAD) [29, 30]. MAD corresponds to the maximum dose that could be absorbed
`if there were a saturated solution of the drug in the small intestine during the
`small intestinal transit time (SITT & 270 min). The bioavailable dose is smaller
`than MAD due to metabolism of components in the portal blood in the liver
`(first pass effect) and in the intestinal mucosal tissue [20]. MAD can be calcu-
`lated from the solubility, S, at pH 6.5 (corresponding to typical conditions in
`the small intestine), the transintestinal absorption rate (Ka), the small intestinal
`water volume (SIWV & 250 mL) and the SITT.
`
`MAD (mg) = S (mg mL–1) ´ Ka (min–1) ´ SIWV (mL) ´ SITT (min)
`
`(1)
`
`Human Ka can be estimated from measured rat intestinal perfusion experi-
`ments [30, 31]. It is related to the permeability (P) through SIWV and the effec-
`tive surface of absorption (Sabs) [20].
`
`Ka (min–1) = P (cm min–1) ´ Sabs (cm2)/SIWV (mL)
`
`(2)
`
`In the absence of active diffusion, permeability is related to the diffusion coeffi-
`cient (D), the partition coefficient K (= cin membrane/cin solution) and the mem-
`brane thickness (d).
`
`P (cm min–1) = D (cm2 min–1) ´ K/d (cm)
`
`(3)
`
`In reality, proportionality between the partition coefficient and the permeability
`is only found for a rather small range of partition coefficients [24, 32]. This is
`because the model of a single homogeneous membrane is an oversimplification.
`The intestinal wall is better represented by a bilayer membrane consisting of an
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`1.4 Phases of Development and Solid-state Research
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`7
`
`aqueous and an adjoining lipid region. Therefore, for highly lipophilic sub-
`stances, the water layer becomes the limiting factor and leads to a decrease in
`permeability as K is increased [33].
`Implicit in Eq. (1) is that the solution stays saturated during the SITT and
`therefore that there is a large excess of solid drug in the small intestine. In de-
`riving this equation as a limiting case, the authors [29] took into account the
`dissolution kinetics of a polydisperse powder and showed how the percentage of
`the dose that is absorbed is influenced by solubility, particle size and permeabil-
`ity. They showed that for highly soluble drugs, as defined above, the percentage
`of dose absorbed is only limited by permeability. For smaller solubilities, the
`dissolution rate and hence the particle size become important factors as well.
`The influence of particle size is greatest for low-solubility and low-dose drugs.
`MAD readily translates into minimal acceptable solubility [30].
`
`Minimal acceptable solubility = S ´ {target dose (mg)/MAD}
`= target dose/{Ka ´ SIWV´ SITT}
`
`(4)
`
`Realistic values for Ka lie between 0.001 and 0.05 min–1 and vary over a much nar-
`rower range than typical solubilities (0.1 lg mL–1 to 100 mg mL–1) [30]. Consider-
`ing these facts and assuming a typical dose of 70 mg, i.e., 1 mg kg–1, minimal ac-
`ceptable solubilities between 20 lg mL–1 and 1 mg mL–1 are obtained. When mak-
`ing these estimates, one has to keep in mind that the assumptions of the model
`break down if there is possible absorption in other parts of the gastrointestinal
`tract or if the diffusivity of the drug is changed due to the meal effect, etc. [34].
`Furthermore, it is important to realize that S represents a “kinetic” solubility. A
`weakly basic drug might be freely soluble in the stomach while its equilibrium sol-
`ubility in the small intestine might be very low. Nevertheless, it may remain in the
`supersaturated state in the small intestine, in which case that “kinetic” solubility
`would be the relevant one for calculating the MAD.
`
`1.4
`Phases of Development and Solid-state Research
`
`Normally, solid-state research and development involves the following stages,
`which may also overlap:
`· deciding whether the uncharged molecule or a salt should be developed;
`· identifying the optimal salt;
`· identifying and characterizing all relevant solid forms of the chosen drug
`substance;
`· patenting new forms;
`· choosing a form for chemical and pharmaceutical development;
`· developing a scalable crystallization process to obtain the desired form of the
`drug substance;
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
`· developing a method to determine the polymorphic purity of the drug sub-
`stance;
`· formulating the drug substance to obtain the drug product;
`· developing a method to determine the polymorphic purity of the drug sub-
`stance in the drug product.
`
`Not all of these stages may be necessary for every drug substance, and the order of
`the stages may be varied according to the specific properties and behavior of the
`drug. Particularly for drugs that are poorly water soluble, polymorphism in formu-
`lations can play a crucial role since it could significantly influence the dissolution
`rate and degree of dissolution required to achieve adequate bioavailability.
`
`1.4.1
`Salt Selection
`
`Clearly, the first decision is whether it is more desirable to develop the un-
`charged molecule or, if possible, a salt thereof (Chapter 12). In general, salt for-
`mation will be possible if the molecule contains acidic or basic groups, which is
`the case for most active molecules. Since making a salt will normally involve an
`additional step in the synthesis and since the molecular weight of a salt will al-
`ways be higher than that of the neutral molecule, salts will only be chosen if
`they promise to have clear advantages compared with the free acid/base. As a
`rule, a salt is chosen if the free acid/base has at least one of the following unde-
`sirable properties:
`· very low solubility in water;
`· apparently not crystallizable;
`· low melting point (typical cutoff 80 8C [35]);
`· high hygroscopicity;
`· low chemical stability, etc.;
`· IP issues.
`
`Low water solubility is relative and always has to be assessed in the context of
`dose and permeability (Section 1.3). A very low water solubility may mean a
`high lipophilicity, enabling efficient passage through membranes, or a very
`large binding constant with the receptor, allowing a low dose. Also, the amor-
`phous state of a neutral molecule may be the best option to get high oral bio-
`availability, provided the amorphous form can be kinetically stabilized over a
`reasonable time scale. Therefore, the decision to develop a salt should be based
`on a head-to-head broad comparison, taking into consideration both in vivo per-
`formance and physicochemical properties. If the decision has been made to de-
`velop a salt, it is obviously important to carry out a broad salt screening and salt
`selection process to identify the optimal salt. Potential counterions are chosen
`based on pKa differences, counterion toxicity (preferably GRAS status [18, 36]),
`etc. (Chapter 12). Desirable properties of the salts include crystallinity, high
`water solubility, low hygroscopicity, good chemical stability, and high melting
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`1.4 Phases of Development and Solid-state Research
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`9
`
`Fig. 1.3 Rough guideline of when the various issues related to solid-state
`properties generally should be taken care of in the development process.
`Depending on company policies, obtained results and other circumstances,
`large shifts are possible. In particular, certain steps may have to be
`repeated due to unanticipated experimental results.
`
`point. The relative importance of these properties may vary from project to pro-
`ject. At this stage it also has to be decided whether co-crystals are to be consid-
`ered. Co-crystals can offer valuable alternatives, especially for very weak bases or
`acids. Very often, salt screening and salt selection are performed in stages: first
`a large number of salts is produced on a microscopic scale and characterized
`with a limited number of methods (e.g., birefringence, Raman, XRD) to identify
`a few promising candidates, which are then produced on a scale of a few
`100 mg and characterized in more detail.
`Different companies perform salt screening in different phases of development.
`Some even move the salt selection process to the research phase [35], but clearly
`the decision on the salt form should ideally be made no later than the beginning of
`the long-term toxicology studies, i.e., at the start of Phase I (Fig. 1.3).
`
`1.4.2
`Polymorph Screening
`
`The objective of the next important step with respect to solid-state development is
`identifying all relevant polymorphs and solvates (Chapter 11), characterizing them
`(Chapters 3 to 7), and choosing the optimal form for further chemical and phar-
`maceutical development. In the absence of solvents and humidity, the thermody-
`namically stable polymorph is the only one that is guaranteed not to convert into
`another polymorphic form. This is why this form is most often chosen for the
`drug product [31]. The disadvantage of the thermodynamically stable form is, of
`course, that it is always the least soluble polymorph (Chapter 2) and therefore
`has the lowest bioavailability. But in most cases this is a small price to pay for
`the very large advantage of absolute kinetic stability. Differences in the solubility
`of various polymorphs are typically lower than a factor of 2 (see Ref. [37] for a re-
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
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`view of literature data), but sometimes as much as a five-fold difference can be ob-
`served [38]. In cases where several enantiotropically related forms exist and where
`the transition temperature is around room temperature, the choice may be diffi-
`cult, but it is based on the same criteria as for all solid forms. The kinetics of in-
`terconversion from one form into the other and the reproducibility of producing
`consistently the same ratio of polymorphs are important.
`Apart from the thermodynamically stable polymorph of a drug substance, hy-
`drates are also very popular components of the final dosage form. Owing to the
`ubiquity of water vapor, hydrates are often the thermodynamically stable form
`at ambient conditions. If a certain hydrate is stable within a rather large range
`of humidities, it may therefore be much easier to formulate the hydrate in a
`controlled way and to subsequently store and package it.
`In a few cases, a metastable form might be preferable [31], normally for one
`of the following reasons:
`
`too low a solubility (and bioavailability) of the stable form;
`1.
`2. high dissolution rate needed for quick-relief formulations;
`3. manufacturing difficulties;
`4.
`IP issues;
`5.
`chemical instability of the thermodynamically stable form due to
`topochemical factors.
`
`(1) If the solubility of the stable polymorph is critically low (Section 1.3) and no
`salt is feasible, several options exist [39]. Liquid-like formulations (emulsions,
`microemulsions, liposomal formulations) or soft gelatin capsules filled with
`solutions of the drug in a non-aqueous solvent may be used. Alternatively,
`a metastable solid form, a solvate or a co-crystal might be selected for devel-
`opment. If a solid form with a higher solubility than the thermodynamically
`stable form is desired, it is often better to use the amorphous form rather than
`a metastable polymorph, provided that the glass transition temperature (Tg) of
`the amorphous form is sufficiently high (Chapter 10) [40]. Firstly, the amor-
`phous form often has a ten-fold or higher increased solubility relative to
`the stable form [41], while metastable polymorphs typically have a less than
`a two-fold higher solubility, as mentioned above. Secondly, it is normally im-
`possible to stabilize a metastable form reliably by excipients, since they can
`only interact with the surface of the crystals of the metastable drug substance.
`This will change the surface free energy, but for crystal sizes larger than some
`tens of nanometers, the contribution of the surface free energy to the total
`free energy is negligible. The best way to stabilize a metastable form kineti-
`cally is to ensure the absence of any seeds of the stable form because such
`seeds have a very large effect on the kinetics of transformation [42]. The amor-
`phous form, however, can be stabilized, for example, by creating a solid dis-
`persion with a polymer [43, 44]. Such a dispersion will be highly kinetically
`stable if two conditions are fulfilled: if it remains in the glassy state under
`the storage conditions, thus blocking all translational diffusion, and if the
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`1.4 Phases of Development and Solid-state Research
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`11
`
`drug substance molecules are molecularly dispersed within the matrix. In any
`case, irrespective of whether a crystalline or disordered metastable form is to
`be developed, very careful kinetic stability studies will be necessary. For amor-
`phous solids, particular attention has to be paid to the lowering of the glass
`transition temperature due to humidity.
`
`(2) In some instances, quick onset of action of a drug is of particular impor-
`tance. In such cases, metastable forms with a higher dissolution rate may
`accelerate the uptake of the drug and may therefore act faster.
`
`(3) Different polymorphs will also have different mechanical properties, such
`as hardness, powder flow properties, compressibility and bonding strength.
`A well-known example is acetaminophen (also known as paracetamol),
`where the thermodynamically stable form (monoclinic form I) cannot be
`compressed into stable tablets while the metastable form II (orthorhombic)
`can as it shows more favorable properties with respect to plastic deforma-
`tion [45]. In very rare cases, this might lead to a decision to develop a meta-
`stable form.
`
`(4) If the thermodynamically stable polymorph is protected by patents, while
`other forms are free, the respective drug substance can be marketed as a
`metastable form without obtaining a license from the patent owner (Chap-
`ter 14) [5].
`
`(5) Generally, the thermodynamically most stable polymorph is also the most
`stable chemically (Chapter 2) [31]. This has been attributed to the fact that
`its density is typically higher, but it could also be explained by its lower free
`energy. Only in extremely rare cases, where the arrangement of atoms in
`the stable polymorph favors an intermolecular chemical reaction, could its
`chemical stability be lower. In such cases, development of a metastable
`form might be advisable.
`
`A very important question is, of course, when a polymorphism screening should
`be carried out and when the choice of form to develop should be made. Since dif-
`ferent solid forms have different properties and may have different bioavailabil-
`ities, it is definitely advisable to select the final form together with the accompany-
`ing formulation before carrying out pivotal clinical studies [19, 46]. It is, therefore,
`critical to have at least identified the thermodynamically stable form along with
`important hydrates by the end of Phase I at the latest (Fig. 1.3). Accordingly, by
`that time a polymorphism screening that is primarily designed to identify these
`forms with a large probability should have been completed. Owing to economic
`reasons and the expected attrition rate of up to 90% of potential drug candidates
`after this stage, a full polymorphic screening, which identifies all relevant meta-
`stable forms as well, may need to be deferred. However, this should only be the
`exception because knowledge of metastable phases, thermodynamic stability as
`a function of temperature and conditions for solvate formation is crucial for the
`design of crystallization and formulation processes.
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`IPR2018-00126
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`Page 11 of 20
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`12
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`1 Relevance of Solid-state Properties for Pharmaceutical Products
`
`While the kinetic stability of dry metastable forms is not much influenced by
`additives, as mentioned above, additives and impurities can influence their ki-
`netic stability in solutions and suspensions [47] by affecting both nucleation
`and growth rates. Therefore, a polymorphism screening that is performed with
`an early batch of drug substance still containing many impurities may provide
`different results from a screening performed with a later, purer batch. In partic-
`ularly unfortunate cases, important forms may not be discovered in the initial
`screening. Therefore, it is highly advisable to repeat at least a limited poly-
`morphism screening with a batch of drug substance produced with the final
`GMP procedure, which has the impurity profile of the product to be marketed.
`Clearly, the unexpected appearance of a new form at a late stage can be disas-
`trous. A very well publicized example is that of ritonavir (Norvir) [38, 48]. When
`it was launched on the market, only form I was known. One marketed formula-
`tion consisted of soft gelatin capsules filled with a nearly saturated solution of
`form I. About two years after market introduction, some capsules failed the dis-
`solution test due to precipitation of a new, thermodynamically more stable form
`of ritonavir (form II). The solubility difference between forms I and II is about
`a factor of 5 [38], which is unusually high. In the end, the original formulation
`had to be taken off the market, and a new formulation had to be developed with
`considerable effort and expense [38]. While this is certainly an extreme case,
`there are many instances of new polymorphs appearing in Phase II and Phase
`III studies, leading to considerable difficulties [49].
`
`1.4.3
`Crystallization Process Development
`
`After selecting the appropriate solid form for