From form to function: Crystallization of active pharmaceutical ingredients (2008)

Since the introduction of aspirin in 1899, and more particularly since the advent of antibiotic “wonder drugs” in the 1940s, society has come to rely on the widespread availability of therapeutic drugs at reasonable prices. It was a tremendous challenge to bring penicillin to market and could not have been done without the simultaneous development of both product and process under the inspired leadership of Howard Florey over a 10 year period starting in the early 1930s, as revealed in the riveting story told by Eric Lax.1 In the interim, much has changed in drug development, but the timelines remain long, and the obstacles to success remain high. For drugs delivered to patients in crystalline form, the physical properties of the active pharmaceutical ingredient (API) including crystal form, size and shape have the potential to impact bioperformance, particularly for low-solubility compounds, where the rate-limiting-step in drug uptake may be the dissolution of the API in the gut. These physical properties of the API are often controlled in the final API crystallization step. Because most small molecule drugs (>90%) are delivered in crystalline form, and currently about 90% of new API's being pursued are classified as having low solubility in water, a well-controlled crystallization of the API is often a vitally important operation in pharmaceutical manufacturing. Moreover, it is a difficult operation because of uncertainty in the crystal forms that will appear, and because of the many challenges associated with scaling-up crystallizations from laboratory to manufacturing scale. Although great emphasis is placed on the therapeutic and chemical discovery aspects of new APIs, it must be emphasized that the successful entities will eventually need to be manufactured. Pisano2 has made a detailed study of the strategic value of process development and concludes that the benefits of a superior manufacturing process can include early product launch and consistent, higher product quality. Most companies seek to minimize manufacturing costs and maximize process portability by applying the simplest manufacturing process capable of producing their drug product with desired attributes. Because only 10% of the compounds in development survive the efficacy and safety hurdles in the clinic and become marketed drugs, there is also great value in minimizing R&D costs (including clinical trials), which are estimated to be about $1 billion per launch, with a remaining life protected on-patent of typically only 6–10 years. In this perspective, we describe the state-of-the-art in API crystal product and process design, highlight barriers that currently prevent the production of better, cheaper crystalline products, and give our best estimate of where the field is going and should go during the next decade. The ultimate efficacy of a drug molecule depends on its interactions with the appropriate target in the human body at the molecular level. However, the delivery of the drug in a safe and economical way partly depends on the properties of its solid-state, at least in those cases involving a solid dosage form. Small molecular drug entities (which typically have molecular mass in the range 200–600) are normally isolated as crystalline or, in some cases, as amorphous solids for delivery, although the ultimate formulation may be a solution or suspension. Crystallinity confers various advantages during isolation, processing and storage of the drug, such as better impurity rejection, improved handling characteristics, such as sticking and flow and, in the majority of cases, better physical and chemical stability. These factors are particularly important in defining a robust processing platform and storage conditions so that a stable product can be delivered to patients. Solid dose API's can be prepared as native free base (or free acid) moeties or as salts; they can be anhydrous, hydrates, or solvates; they may be crystalline or amorphous; they may even be prepared as a single component or as a cocrystal. Each has its advantages and disadvantages. Most critical to the performance of a drug in humans is its plasma concentration profile, frequently referred to as bioavailability. It is the fraction of administered dose of drug that reaches systemic circulation and is an important pharmacokinetic property of the solid-state of the drug. Hence, the formulation needs to be optimized to ensure that sufficient drug will be available to engage the target in humans and, hence, be efficacious. Since the crystalline state is thermodynamically more stable than the amorphous state, its solubility and dissolution rate can be expected to be lower than that of the amorphous phase.3 In addition, the solubility and dissolution rate of a more stable polymorph (most crystalline solids are capable of existing in several molecular packing configurations called polymorphs, e.g., carbon has two-diamond and graphite) will be lower than that of a less stable form. While this could potentially have a negative impact on bioavailability (in cases where bioavailability is limited by the solubility and/or dissolution rate), it is still preferable to develop the polymorph with lowest free energy into a drug product due to physical stability considerations. An effective way to anticipate the existence of multiple forms, including solvates and hydrates, is to preinvest in experimental crystal form screening, which may also include salt screening in cases where the drug molecule is a free acid or free base. Almost every pharmaceutical company has some form of high-throughput approach to perform these screens. There have also been some efforts at so-called “polymorph predictions”,4, 5, 6, 7 but this is a very nascent field in terms of being practically relevant to current drug development. The only example the authors found of a stable crystalline form that was predicted in silico, and subsequently produced experimentally in the laboratory is the case of racemic progesterone.8 A similar case for a marketed drug has not been found. This is a reflection of the immense complexity of anticipating packing arrangements of organic molecules in crystal lattices, our inadequate understanding of subtle yet important nonbonded molecular interactions (e.g., van der Waals interactions, hydrogen bonds, zwitterionic interactions, etc.) that can influence such packings and inadequacies in accurate energy calculations of molecular crystals. For example, the energy difference between polymorphs could be smaller than the accuracy level of parametric force-fields.9, 10 Ab initio methods are not yet capable of accurately computing energetics of even rigid molecules. This fascinating theoretical problem is sure to engage the imagination of academics for the foreseeable future and, should a successful method be developed, could change the way polymorph screening is conducted in the pharmaceutical industry. However, a pessimistic view of the whole process involves asking the question — Even if free energies could be adequately calculated for crystals as a function of temperature, will this lead to a successful prediction? For practical purposes, one would want to predict the experimentally observed structure, which need not exactly coincide with the thermodynamically most stable structure.10 Another important factor to consider when selecting the API phase is that the pH-solubility profile of a drug with a pKa in a pH range that is physiologically relevant can play a major role in determining pharmacokinetics. For example, the HIV protease inhibitor, indinavir (Figure 1), has a solubility of 0.02 mg/mL at pH 7.4, which increases to 60 mg/mL at pH 3.5 due to protonation of the pyridinyl nitrogen, i.e., an acidic environment increases the probability of absorption of indinavir.11 However, HIV-infected patients frequently suffer from low-levels of HCl in the stomach. Hence, it is critical to develop an acidic salt of indinavir, such as the sulfate, which is the commercially marketed solid form, to ensure optimal serum concentrations for anti-HIV activity. (a) Structure of indinavir sulfate ethanolate. (•) pH-solubility and (□) pH-logP profile for indinavir, where P is the octanol-water partition coefficient for indinavir.11 Crystallization often represents a convenient and scalable method to purify a drug substance, and the extent of impurity rejection could depend significantly on the particular crystal form that is isolated. The purifications of dirithyromycin,12 and (R, R)-formoterol tartrate,13 represent two examples, where it was possible to vastly improve impurity rejection by selective crystallization of an acetone solvate in the penultimate step in the first case, and a high-temperature hydrated crystalline form in the second. In both cases the subsequent processing step involved the isolation of an anhydrous polymorph of the API through a solvent-mediated crystal form conversion in which the less stable form dissolves, and the more stable form simultaneously crystallizes, as explained in the context of other systems by Cardew and Davey,14 and by Veesler et al.15 The intriguing case of ritonavir (an important ingredient in the AIDS medication cocktail) is presented as a case study to justify preinvestment in crystal form screening, in order to improve the probability of discovering the most stable polymorph early in the drug development cycle.16 In this instance, the formulated product, Norvir™, a semisolid capsule, failed dissolution tests after being launched in the market due to the appearance of a new, more stable crystalline polymorph of ritonavir, Form II, which possessed a lower thermodynamic solubility than the marketed Form I. Abbott was forced to reintroduce the product formulated with Form II, but encountered serious challenges in maintaining the drug supply of this life saving treatment for AIDS. The new form was believed to have been templated by the production of a degradate of ritonavir base, the cyclic carbamate, with an analogous structure.17 This case highlights the difficulty faced by the industry in forecasting with any scientific certainty whether the crystal form in development is the most stable form, hence, resistant to form changes as drug development goes through clinical trials followed by large-scale manufacture of the product during the marketed lifetime. It also exemplifies the highly stochastic nature of nucleation, which may lead to the undesirable scenario in which an undiscovered form appears during late-stage development or manufacturing. Another aspect of crystal forms in an emerging area that has recently received a great deal of attention is that of cocrystals. These represent crystals containing two or more distinct components that are held together by either hydrogen-bonding or strong dispersive interactions. Solvates and hydrates are typically excluded from this list. Such crystal forms could offer advantages in terms of bioavailability,18, 19 stability, and the ability to extend the product portfolio if sufficient advantages can be demonstrated by developing the cocrystal compared to the neutral form. Certain crystal habits are notoriously difficult to handle in both the laboratory and in manufacturing — needles and flakes being the worst. While it is normal to have a suspension density of 15 wt % solids for equant-shaped crystals, it is difficult to reach even 5 wt % for needle-shaped crystals. Moreover, needles and flakes are difficult to filter, dry, handle in powder form, and formulate. It is well-known that crystals grow in a variety of shapes in response to both internal (crystal structure) and external factors. Some of these factors can be manipulated (e.g., solvent type, impurity or additive concentrations, solution temperature and supersaturation, etc.) by crystal engineers to steer crystals toward a target shape or away from undesired shapes. The importance of crystal shape to processing and product quality/functionality has been discussed in the context of ibuprofen by Gordon and Amin.20 The primary interest in this system is the existence of high-aspect ratio rods when grown from nonpolar hydrocarbon solvents, such as hexane or heptane. Equant, low-aspect ratio crystals are formed when grown from polar solvents, such as methanol or ethanol. The resulting crystals have better dissolution behavior and improved processing properties relative to the rods grown from nonpolar solvents. This was discovered by researchers at the Upjohn Company, who patented the change in solvent as a process and product improvement.20 It is well-known that different polymorphs may exhibit substantially different crystal morphologies. For example, Figure 2 presents an instant in time during the solvent-mediated conversion of orthorhombic paracetamol (needles) to the monoclinic form, which exists as prisms and plates in benzyl alcohol. Solution mediated conversion of orthorhombic paracetamol to monoclinic paracetamol in benzyl alcohol. The scale bar represents 250 μm.21 Dramatic changes of crystal shape can also be induced by changes in solvent or solvent mixture (see Winn and Doherty22 for a review of solvent effects) and by the presence of quite small amounts of surface active impurities in solution that act as growth inhibitors for certain crystal planes. Growth inhibitors may be added deliberately to modify the crystal shape, or may be present as a result of the manufacturing conditions (e.g., due to reaction chemistry). A classic example of this is the case of paracetamol (also called acetaminophen) crystallization, whereby small amounts of reaction byproducts, such as metacetamol, change the paracetamol crystal shape from equant to needle-like.23 Changes in supersaturation may also induce changes in shape, but this is typically not as dramatic (e.g., again the case of paracetamol).24 Consequently, the potential for changes in crystal shape is although this is an area that has not been as by drug companies as one In the authors are not of any marketed drugs for which the API shape has been by the of a growth to the final API the growth inhibitors that are at play in API crystallizations are of chemical and there is limited to predict the extent to which low-levels of these impurities may crystal may the rate of plasma uptake of an API when the process is dissolution rate The may also API processing such as and and product formulation such as and which such as and the bioavailability perspective, small are as they but small can be to a manufacturing perspective, are but not so as to in the formulated product, which can be a particular for a or are to be as they have a higher to and often have flow In most cases, about an optimal size are for both and the is by the between crystal growth and nucleation, which is controlled by the level of supersaturation during the of the This is whether the supersaturation is by addition, or chemical et present an example of a crystallization in for which a of over the could be by selecting an appropriate The profile whether or growth at instant of time during the the system those crystals have a to and are the system they so one is to a in of API often some of size subsequent to crystallization in order to some or of the needles or rods into smaller aspect ratio the size significantly from that during crystallization, or a more of emerging in the is applying in the range in order to and crystal aspect cases of this are in the including an by researchers at who that such an approach has been to the size of API from an size of to smaller than The development of a process to the API is by the to the sufficient product to isolation of the crystal form, which is typically very the most thermodynamically stable form, a target and crystal shape, as these may both bioavailability and a with final concentrations typically for 10 5 wt and reasonable time for the crystallization, as as for the associated and these factors would be as with being critical to ensure and are frequently on their impact on chemical stability and bioavailability. While factors are not expected to have impact on the the of in an to seek to the of particularly for these factors are not and one may it to the as it may there are some cases where process development a of The other critical factor that on this is the need to develop very often with very small of in order to early formulation development toward a market a placed on to market as as the is to the process development the critical because the majority of the being are for compounds that will become marketed drugs, there exists a strong to applying a approach to this process development. this perspective, there is great value in it the first that the solution represents a where two of the critical being optimized are time and In to a is also placed on a of scientific understanding of the process during development, as this can be into under the new While at first these two our ability to both of these may be by the of scientific and new such as process process including and and in the area of The of these a as processing has found limited in the pharmaceutical industry relative to the of the chemical and there are many who that this has been a While there are of API as the crystallization of et API have to or as the industry Because have the potential to offer and/or safety or to even not interest in this has significantly over the years. The most example of this interest is the recently for by a from highly is the for its potential to offer advantages in the of many chemical in However, the of this to crystallization been with the majority of the in the area on of molecules. The small (which give their are highly to and practical on the size of the that can be The of any process development should be a scalable For crystallization it is the of these that is often most difficult to or to the majority of final API crystallizations have been conducted in involving a of nucleation, and the of the of these are highly on the as to supersaturation, which can and can lead to the is the that is notoriously to because as one between is difficult to and one can not both (which and, and per (which and of to the a of these from laboratory to often in changes in both and crystal in could some of this uncertainty by the and into the the state-of-the-art crystallization that can predict process performance In response to this of the majority of have on to the size and shape, the to ensure target performance in patients. However, or has a of the present serious due to crystal may be to the the product from is often in and/or highly processing and most is a very These are the industry to that size and shape into the final crystallization so that can be from such approach is to develop in which nucleation, and are are critical to minimizing surface and in order to at the where or is being The first can be by a of in is often referred to as a process in which a of the final from is in the to as for more amounts of surface area 2 can be In either case, by sufficient supersaturation to ensure a growth one can final API size by the to the success of this approach is a step that from to The is by to the system a to the or other such one can very in the this from the which can be and to and solids suspension. In some cases, particularly when surface area is and the growth are very can be an and since surface area and the it is an that must be can be through energy to the system a or other into the In the case of compounds, the should be with a to the or for such this approach to API has become the and from laboratory the way to scale has been the of and process by such as the only this a to be during the crystallization, but the of crystallization best the of crystal forms or impurities that could product quality. For also is In the field of pharmaceutical this has than it The that are a strong for companies to their and the ultimate impact of those on the patients under the new a on A understanding of the crystal form and crystallization of drug molecules will several of the drug development to into through salt impurity rejection in for a drug product with stability and and the potential to a product on of this is the need to develop drugs more and more than in an environment that has become the challenge that drug companies is the need to minimize process development and manufacturing costs and to reach simultaneously these is of great value to both the patients and the pharmaceutical industry — the ultimate of success being drugs the market and to the patients who need than believed The of this was to highlight the complexity of the the the in or and for in the development of pharmaceutical crystallization While many of the that may the in this field are in the early of their development, most are from to handle the complexity of drug molecules being from process in large-scale or that have the potential to API product and process to the most salt form or cocrystal particularly with an understanding of the solubility and possible form conversion in dissolution such as and initio of the polymorphs of an API in their relative order of stability, scientific understanding of the of impurity rejection by solvates and hydrates compared to the anhydrous free base or to crystal size or shape in a process to and better understanding and tests for and late-stage polymorphs, those in formulated or solid Some of these may be the pharmaceutical but most are to be the of between and industry. and and for to their on API product and process the for of in crystal under