INTRODUCTION
Many pharmaceutical solids can exist in different physical forms. It is well recognised that drug substances can be amorphous (i.e. without regular molecular lattice arrangements), crystalline, anhydrous, at various degrees of hydration or solvated with other entrapped solvent molecules, as well as varying in crystal hardness, shape and size. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystalline solid adducts containing either stoichiometric or non-stoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates. Polymorphs possess different lattice energies and this difference is reflected by changes in other properties. For e.g. the polymorphic form with lowest free energy will be the most stable and possess the highest melting point. Other less stable (metastable) forms will tend to transform into the most stable one at rates dependent on the energy difference between the metastable and the stable form.
Polymorphism was defined as the ability of any compound to crystallize as more than one distinct crystal species. However, in physical pharmacy the word ‘polymorphism’ is nowadays often used to cover a variety of solid forms of active pharmaceutical ingredients (APIs) and excipients including crystalline, amorphous, and also solvate/hydrate forms. Accordingly, the activity of generating, isolating and analysing different solid forms of an API is known as polymorph screening. Solid form screening can be approached experimentally and computationally.
In the crystalline state (polymorphs, solvates/hydrates, co-crystals), the constituent molecules are arranged into a fixed repeating array built of unit cells, which is known as lattice, whereas in the amorphous state there is disorder in the arrangement.
The solid forms of a given API can have significantly different physicochemical properties that can affect its performance.
Physical properties that differ among various solid forms
If solubility and/or dissolution rate are dependent on the solid form, the bioavailability of the API can be affected. This is a particularly important note when developing BCS class II APIs (low solubility and high permeability) with dissolution dependent bioavailability.
Examples of APIs with bioavailability problems due to solid-state phenomena are carbamazepine and ritonavir. Mechanical property differences can affect processing behaviour, and this is the case, for example, with paracetamol: direct compression of form II is feasible, whereas with form I, binder excipients have to be used. Also different forms of theophylline and sulfamerazine have been reported to show different processing characteristics.
Polymorphs and/or solvates of a pharmaceutical solid can have different chemical and physical properties such as melting point, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapor pressure, and density. These properties can have a direct impact on the process-ability of drug substances and the quality/performance of drug products, such as stability, dissolution, and bioavailability. A metastable pharmaceutical solid form can change crystalline structure or solvate/desolvate in response to changes in environmental conditions, processing, or over time.
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 regulation 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.
Certain drugs e.g. novobiocin are unstable in the amorphous form and reverses to a crystalline form when suspended in an aqueous medium, with a consequent reduction in dissolution rate. Chloramphenicol palmitate an ester, which is used as a source of chloramphenicol in oral preparations exist in three crystalline forms and one amorphous form. Only one of the polymorphs is hydrolyzed rapidly in the gut with the formation of chloramphenicol, the remainder is inactive. Polymorphism affects drug absorption.
Polymorphism is remarkably common, particularly within certain structural groups: 63% of barbiturates, 67% of steroids and 40% of sulphonamides exhibit polymorphism.
Methods to generate various solid forms:
CHARACTERIZATION OF POLYMORPHS
A number of methods have been employed for characterizing polymorphs in pharmaceutical solids. Polarizing optical microscopy and thermomicroscopy have proven to be useful tools. Thermal analysis procedures, such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), can be used to obtain additional information, including phase changes, and to deduce whether each isolated form is a solvate or anhydrate. These thermal methodologies are employed to distinguish between enantiotropic and monotropic systems. For an enantiotropic system, the relative stability of a pair of solid forms inverts at some transition temperature beneath the melting point while a single form is always more stable beneath the melting point in a monotropic system.
Methods to study solid-state properties:
The utility of solid-state spectroscopy for characterization of polymorphic systems is becoming exceedingly important. Nuclear magnetic resonance (NMR), infrared absorption, and Raman spectroscopy are used to study crystal structures. These methods require that either the nuclei of the pair of substances being examined exist in magnetically non-equivalent environments or the vibrational modes are sufficiently different between the structural forms to permit differentiation.
It should be emphasized that the definitive criterion for the existence of polymorphism is via demonstration of a non-equivalent crystal structure, usually by comparison of the x-ray diffraction patterns. Microscopy, thermal analysis methodology, and solid state NMR are generally considered as sources of supporting information.
PROPERTIES OF POLYMORPHS
Solubility and Dissolution
The solid state characteristics of drugs are known to potentially exert a significant influence on the solubility parameter. Polymorphs of a drug substance can have different apparent aqueous solubility and dissolution rate. When such differences are sufficiently large bioavailability is altered and it is often difficult to formulate a bioequivalent drug product using a different polymorph. Higher dissolution rates and solubilities are obtained for metastable polymorphic forms. For example, the metastable forms of chloramphenicol palmitate and chlortetracycline HCl exhibit improved rate and extent of bioavailability. In some cases such as novobiocin, amorphous forms are more active than crystalline forms.
Solubility at a defined temperature and pressure is the saturation concentration of the dissolved drug in equilibrium with the solid drug. Aqueous solubility of drugs is traditionally determined using the equilibrium solubility method that involved suspending an excess amount of a solid drug in a selected aqueous medium. The equilibrium solubility method may not be suitable to determine the solubility of a metastable form, since the metastable form may convert to the stable form during the experiment.
When the solubility of metastable forms of a drug substance can not be determined by the equilibrium method, the intrinsic dissolution method may be useful to deduce the relative solubilities of metastable forms. Use of the intrinsic dissolution method assumes that the intrinsic dissolution rate is proportional to the solubility – the proportionality constant being the transport rate constant, which is constant under the same hydrodynamic conditions in a transport-controlled dissolution process.
Polymorphic differences and transformation that result in different apparent solubility and dissolution rate are generally detected by dissolution testing. This test provides a suitable means to identify and control the quality of a product from both bioavailability and (physical) stability perspectives. When solubility and dissolution rate of the relevant polymorph forms are sufficiently high and controlled via dissolution, regulatory concerns with respect to bioavailability and stability are minimum. The Biopharmaceutics Classification criteria of high solubility and rapid dissolution should be considered in regulatory decisions.
Stability and Manufacturability
Polymorphs of a pharmaceutical solid may have different physical and solid state chemical (reactivity) properties. Stability is a very important property of a solid form, considering that raw materials and pharmaceutical products may be stored for prolonged periods and the solid state must remain unchanged. It is known that only one form of a pure drug substance is stable at a given temperature and pressure with the other forms, termed metastable, converting at different rates to the stable crystalline form. The most stable polymorphic form of a drug substance is often used because it has the lowest potential for conversion from one polymorphic form to another while the metastable form may be used to enhance bioavailability. Gibbs free energy, thermodynamic activity, and solubility provide the definitive measures of relative polymorphic stability under defined conditions of temperature and pressure. The relative polymorphic stability may be determined by an iterative examination of the relative apparent solubility of supersaturated solutions of polymorphic pairs. Since the rate of conversion to the more stable form is often rapid when mediated by the solution phase, the less stable polymorph with the greater apparent solubility dissolves, while the more stable polymorph with the lower apparent solubility crystallizes out upon standing.
Solid-state reactions include solid-state phase transformations, dehydration/desolvation processes, and chemical reactions. One polymorph may convert to another during manufacturing and storage, particularly when a metastable form is used. Since an amorphous form is thermodynamically less stable than any crystalline form, inadvertent crystallization from an amorphous drug substance may occur. As a consequence of the higher mobility and ability to interact with moisture, amorphous drug substances are also more likely to undergo solid-state reactions.
In addition, phase conversions of some drug substances are possible when exposed to a range of manufacturing processes. Milling/micronization operations may result in polymorphic form conversion of a drug substance e.g. digoxin, spironolactone. In the case of wet granulation processes, where the usual solvents are aqueous, one may encounter a variety of interconversions between anhydrates and hydrates, or between different hydrates. Spray-drying processes have been shown to produce amorphous drug substances. However, phase conversions should not be of concern if they occur consistently. Transition during compression occurs for phenylbutazone and some sulphonamides.
Reversion from metastable forms, if used to the stable form may also occur during the lifetime of the product. In suspensions, this may be accompanied by changes in the consistency of the preparation which affects its shelf life and stability. Such changes can often be prevented by additives such as hydrocolloids and surfactants which appear to poison the crystal lattice.
Metastable forms are sometimes deliberately chosen – usually for better solubility and thus bioavailability. Solid form screening is a regulatory requirement for new pharmaceuticals.
Solid form screening – an industry perspective
In the last decade, big steps have been taken towards the understanding and control of solid forms of APIs. The widespread interest stems not only from the scientific considerations, but also due to the recently emerged regulatory and IP aspects in this field. Both innovator and generic companies have been trying hard to take intellectual gains from the discovery of new solid forms. As a result, solid form patent litigations have become a bottleneck for both sides, which takes many efforts and puts financial burden on the companies.
The specification on polymorphic purity is very important if the API has solubility-limited bioavailability and/or is prone to solid state transformations during processing and/or storage. Therefore, once a new API is chosen for potential development, it is imperative to screen for the solid forms it may possess, and to identify the most suitable one with respect to solubility and stability as early as possible. However, there is no method that can provide absolute confidence that the ideal solid form has been obtained, and sometimes the final form used in the product may indeed arise at the later stages of development. Atorvastatin was initially formulated as an amorphous salt during the development phase. However, it was reported that during Phase III clinical studies, the salt crystallised and its properties changed, which compelled the developer, Warner–Lambert, to conduct additional bridging studies to demonstrate acceptability of the new product relative to that used in the pivotal registration studies. These kinds of events are costly, consuming more development time as well as resources. As such innovator companies are free to choose any suitable solid form as long as there are no IP issues involved, which is highly unlikely during early stage as knowledge regarding the API would normally have remained within the company itself. The knowledge generated by conducting solid form screening can provide the innovator company an opportunity to build a patent portfolio around different forms and therefore a means to enhance product lifecycle management.
Innovator companies have tried to protect solid forms by patents and have gained extra years for the product beyond the expiry of the basic molecule patent. One of the earliest cases of this kind was that of ranitidine hydrochloride, in which GSK had patent protection for form II even though the basic molecule patent had expired. Although the generic companies were able to launch products with form I, the form II patent helped postpone the generic entry.
In a hypothetical case where the solid form patent is the only limiting factor for the generic entry, generic firms can launch their product if they can discover new a solid form which does not have IP protection and has suitable characteristics for product development. This was the case when Teva found a way around Merck’s patents on its crystalline form of alendronate (the active ingredient in the blockbuster Fosamax®) and was able to launch generic version much earlier. Thus, by patenting a maximum number of possible solid forms, innovators can block this route, even though these solid forms would not be used in the pharmaceutical product.
List of some molecules having solid form patent(s) listed in the Orange Book:
The case where an alternative solid form patented by another company has better characteristics can also have major implications. An example of such is topiramate sodium where J & J ended up licensing and paying royalties for the trihydrate form developed and patented by Transform Pharmaceuticals. After the launch of a dosage form by the innovator, a new solid form can help development of novel drug delivery methods with different release profiles and routes of administration. This is particularly important for APIs whose poor solubility is the main hurdle in the development. The above discussion exemplifies the importance of solid form screening for innovator companies. Extensive solid form screening can not only provide them with scientific advantages, but also help meet regulatory requirements and maximise returns from drug development by means of IP.
Importance of Polymorphism in Pharmaceutical Formulations
Polymorphism has achieved great significance in recent years due to the fact that different polymorphs exhibit different solubilities. In the case of slightly soluble drugs, this may affect the rate of dissolution. As a result, the polymorph may be more active therapeutically than another polymorph of the same drug. E.g. the polymorphic state of chloramphenicol palmitate has been shown to have a significant influence on the biological availability of the drug. Chloramphenicol palmitate exists in three crystalline forms designated A, B and C. At normal temperature and pressure, A is the stable polymorph, B is the metastable polymorph and C is the unstable polymorph. The unstable polymorphic form of chloramphenicol palmitate is too unstable to be included in a dosage form. However, the metastable form is sufficiently stable to permit its incorporation in s dosage form. It was shown that the extent of absorption of chloramphenicol increased as the proportion of polymorphic form B of chloramphenicol palmitate increased in each suspension. Stable polymorph A dissolves so slowly and consequently so slowly to chloramphenicol in vivo that this polymorph is virtually without biological activity. The importance of polymorphism to the gastrointestinal bioavailability of chloramphenicol palmitate is reflected by a limit being placed on the content of the inactive polymorphic form A in Chloramphenicol Palmitate Mixture BP.
Polymorphism can also be a factor in suspension technology. Cortisone acetate has been found to exist in at least five different forms, four of which were found to be unstable in the presence of water and change to a stable form. Since this transformation is accompanied with a kind of caking, it is required that the drug be in stable form before suspension is formulated. Heating, grinding under water and suspension in water are all factors that affect inter conversion of the different cortisone acetate forms.
Fats and waxes tend to expand when they melt and contract when they change from the metastable to stable polymorphic form. The dilation or expansion of a sample confined in a dilatometer can be expressed in terms of specific volumes in ml/g, which can be plotted against the temperature to yield dilatometric curves as shown below.
The dilatometric analysis of theobroma oil has been represented in the figure below where the effect of slow and shock cooling are observed.
The shock cooled theobroma oil showed an initial rapid expansion followed by a contraction due presumably to the change from the metastable to the more dense and more stable polymorphic form. Carbowax 1500 is not significantly affected by shock cooling, hence does not appear to exhibit polymorphism.
It has also been pointed out that the different crystal structures of polymorphic forms of the same substance will cause a difference in the thermodynamic activities of the polymorphs. This is of importance in pharmacy since many drugs exhibit polymorphism and their activities will govern their stabilities and rates of solution, thus one may be more stable than the other. Similarly one may show a grater rate of solution and may therefore be absorbed from the GIT at a greater rate than the other forms, and so produce a higher plasma concentration.
Related Phenomena
Polymorphism deals with phase equilibria in systems of one component. There are terms related to phase equilibria in systems of two components containing a solid and water vapour. They include: efflorescence, exsiccation, deliquescence and hygroscopy.
- Efflorescence: This is commonly the loss of water by hydrated substances to the atmosphere in order to attain equilibrium. The vapour pressure of atmospheric water vapour is 13.33 x 102 n/m2 at 293K. Any hydrated substance possessing a vapour pressure greater than this will tend to lose water to the atmosphere so as to achieve equilibrium. This phenomenon is referred to as efflorescence. The process of hydrated substances turning to anhydrous or to a lower hydrate form is also known as efflorescence e.g. the change of Na2CO3 decahydrate to anhydrous or to the monohydrate. However, the vapour pressure of hydrated salts, hence, the rate of efflorescence of such salts is dependent on the temperature (directly proportional). Hence, increase in temperature can be used to facilitate efflorescence.
- Exsiccation: The process of accelerating the rate of efflorescence by increasing the temperature of a hydrated salt is termed exsiccation. In using storage containers therefore, care should be taken to use containers that minimize the loss of water vapour from compounds, which will help to reduce the instabilities that result from efflorescence in such compounds. Copper sulphate is also another example of an efflorescence drug.
- Deliquescence and Hygroscopy: These are used to refer to the absorption of moisture from the atmospheree by substances. Whereas in deliquescence the more hydrated forms turn into a liquid, they remain solids in hygroscopy. However, the more hydrated form must still possess vapour pressure lower than the surrounding atmospheric pressure, otherwise the new form will start efflorescence to get back to the initial state. E.g. of deliquescence salts are NaOH, KOH, sodium lactate and K2CO3, while examples of hygroscopic salts are exsiccated Na2SO4, NH4Cl and squill. Precautions during storage of such materials involve storing at a moisture free environment within the container. The containers should be kept well closed and well filled. A drying agent e.g. silica gel may be packed along with the product. There may however be an indicator to show when the drying agent becomes ineffective.