Solid State Chemistry

The impact on drug development, manufacturing, and IP protection

By Jan-Olav Henck and Stephen R. Byrn
Aptuit Purdue University

Solid state chemistry — with wide-ranging implications for late stage discovery, active pharmaceutical ingredient (API) manufacture, formulation, manufacturing of final dosage form, protection of intellectual property and lifecycle management — is becoming an increasingly important component of the drug development process.

Solid state chemistry is the study of the synthesis, structure, and properties of solid phase materials and deals primarily with the unique crystallographic and microscopic features of a chemical which result in macroscopic chemical properties.

A chemical compound can exist in multiple forms including crystalline and amorphous solids — a phenomenon known as polymorphism. Crystalline solids display a highly regular, repeating arrangement of atoms or molecules; 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.

Other solid form types include solvates, hydrates, salts and cocrystals. 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. In a salt, a basic or acidic molecule is paired with a counter-ion (Figure 1).

When polymorphism results from differences in the conformation of molecules in the solid state, it is called conformational polymorphism. Different crystal types resulting from hydration or solvation are often referred to as pseudopolymorphs.

Although chemically identical, polymorphs of the same compound can differ dramatically in their physical and chemical properties, including solubility, density, dissolution rate, stability, color, hardness, and compressibility.1 In chemical elements this phenomenon is called allotropism. The concept of allotropism is readily 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.

API Polymorphs

It is estimated that 30-50% of APIs exist in at least two polymorphic forms. At Aptuit, the highest number of solid forms we have identified for a single compound is 87. Because the particular crystal structure of a chemical compound can confer distinctive properties, polymorphs of the same API can differ dramatically in bioavailability, dosage form stability and manufacturability. Variations in properties can also lead to broad ranging differences in levels of gastric irritation, toxicology results, and clinical trial results. Ultimately, both safety and efficacy can be impacted by properties that vary among polymorphs.

Adding to this complexity is the fact that new crystalline forms can appear without warning. Over time or under different conditions, existing polymorphs of a compound can convert to new forms with different properties. Changes in a manufacturing process can also result in the appearance of new crystal structures. Encountering a new solid form during late stages of development can delay filing. If a change happens after a drug is on the market and results in a form that cannot be manufactured or dispensed in the same way or does not have an equivalent bioavailability, it may result in withdrawal of the product.

Despite the challenges presented to development and manufacturing processes, there is good news. API polymorphs can offer important opportunities and advantages in the areas of intellectual property and lifecycle management.

Impact on Development and Manufacturing

It is well known that the amorphous state of a compound shows a higher apparent solubility compared to the crystalline forms. Because the amorphous state is more soluble, use of this form in early clinical studies can prove advantageous for making early determinations about a compound’s toxicity profile. The solubility benefit comes with a price, however, and that is stability. Amorphous materials are less thermodynamically stable than their corresponding crystalline forms and as a result, most pharmaceutical companies would prefer to market a crystalline form of an API.

It is a time-consuming, labor-intensive process to attempt to identify all possible solid forms an API can adopt and there are no guarantees that all forms will be discovered. However, a thorough screening of polymorphs early in the development process is essential in order to:

•Make the same form for clinical material and commercial API,

•Develop a crystallization process that assures control of solid form, and

•Produce a drug product with solid form stability through expiration

Through the screening process, we identify as many different polymorphic forms as possible, understand the conditions under which each is produced, and profile the long-term stability of each. This information combines to guide selection of the optimal form that will ensure efficacy and control consistency throughout formulation and manufacture. If a form switch is made later in development, expensive and time-consuming bio-equivalence studies may be required.

A delay in understanding solid form issues can result in 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 clinical trials are relevant. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines require a search for solid forms, comparison of properties that might affect product efficacy, and, if appropriate, setting of solid form specifications.

A Three-Stage Approach

In our experience, the best approach to polymorph screening 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 potentially patent as many of the forms that where found of a high-potential drug for our clients. 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 funds.

Through this process, it is imperative to identify, among all forms that have been found, the most thermodynamically stable crystal form at room temperature as this will be preferable for manufacturing. The polymorph screen may also reveal metastable polymorphs that can revert to a more stable form over time and in doing so, display different properties.

The process of polymorph screening is truly an empirical exercise in which experience plays an enormous role. Unusual and unexpected results can arise and when properly identified, not only help avoid costly delays in development, but also offer important opportunities for the protection and extension of intellectual property. This “hands on” expertise and ever-evolving analytical techniques are now being combined with predictive models to facilitate polymorph screening.

At Aptuit, we’ve developed computational tools based on the data we have collected on hundreds of drug compounds and thousands of polymorphs. These models are used to predict what solid forms are likely to exist as well as their expected properties. We are able to calculate different stages of energy of crystals forms and theoretically rank them as a function of their energy. We can also calculate a theoretical x-ray diffraction powder pattern for each predicted polymorph. X-ray powder diffraction is one of the most powerful methods for the study of crystalline and partially crystalline solid-state materials. Each crystalline form has a unique powder diffraction pattern that can be used to identify the presence of that form within a sample.

When the actual polymorphism screen is conducted, those powder patterns can be compared to the predicted patterns. If patterns from the actual screen don’t have a corresponding theoretical pattern, a second look is warranted, as a form is likely to have been missed in the screening process.

We also have developed extremely powerful indexing software that allows us to identify if a powder pattern of a particular sample contains only one crystal or exhibits a mixture of polymorphs.

Controlling the Solid Form

It is critically important to control the solid form during API synthesis in order to demonstrate complete process control to regulatory agencies and maintain the desired drug properties.

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.

The potential for solid form variation extends well beyond API production into 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 also occur in the final dosage form over time. Suspensions, including those in transdermal patches, are particularly vulnerable because they provide a low-energy pathway for form interconversion. 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.

The phenomenon of “polymorphic shift” can have serious implications. This was the case with ritonavir, an HIV protease inhibitor marketed by Abbott Laboratories as Norvir; a previously unknown, thermodynamically more stable polymorph appeared unexpectedly in marketed capsules. This highly publicized story illustrates the need for early and comprehensive identification of solid-form diversity of APIs.

During development and initial manufacture of ritonavir, only one “monoclinic” crystal form was known.2 The form was not sufficiently bioavailable in the solid state by the oral route, so the product was formulated as a liquid-filled capsule. Two years after entry into the market, the drug started to fail dissolution tests and was precipitating out of the capsules. Evaluation by Abbott and SSCI (a division of Aptuit) revealed that a second crystal form of ritonavir had appeared, was more stable, and was < 50% as soluble as the original form. The second form continued to spread and the first form could no longer be synthesized. The resulting change in bioavailability led to withdrawal of the gelcap dosage form from the market while reformulation was completed.

Substantial effort and investment was required to understand the nature of the polymorphic shift, reformulate the drug, and identify strategies to regenerate the original form. A new formulation of Norvir was eventually developed and launched.

Identifying Solid Form Problems

Whenever there is a specification failure in a drug product or 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. Changes in the appearance of gelcaps or cracking of tablet coatings can indicate solid form problems. A number of analytical techniques can be used to identify solid form in API; some are even able to determine the solid form of API in intact final dosage form.

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.

Now for the Good News

Polymorphism does have a positive side. 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, extending the lifecycle of a drug.

In many cases, a drug developer will file patents covering various solid forms of an API for which a composition ofmatter patent has been secured. Filed a few years after the original composition of matter patent, these patents can extendthe protection of intellectual property once the compositionof matter patent expires and can prevent a competitor from

developing a generic version of the API using the patented structure.

The anti-ulcer drug Zantac offers a classic example of the value of patenting polymorphs. Glaxo (now GlaxoSmithKline) patented a polymorph of ranitidine hydrochloride in 1978 and a second polymorph in 1985 (Table 1).3 When the original patent expired, competitors sought to market their own versions, but the existence of the second patent allowed Glaxo to continue marketing the drug and delay the launch of generic versions.

Alternative solid forms with differing properties can also be leveraged to design a range of drug formulations. For example, by using different solubility profiles, a drug formulation that must be taken two or three times a day can change to a once-a-day (or -week or -month) formulation, which can have a significant impact on patient adherence and in turn, increase revenue derived from the brand.

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.

Perspective

A thorough scan of the solid form landscape and comprehensive identification of polymorphs is vital to both scientific and financial success. Awareness of different solid forms, their properties, and the ability to control of these forms can help avoid costly and time-consuming delays across the entire development continuum.

Beyond the impact on development and manufacturing, a strategic approach to intellectual property protection that leverages polymorphs can help extend a drug’s lifecycle, delay the availability of generics, and strengthen revenue streams.

Co-crystals

Increased attention is being paid to the use of co-crystals to alter the physical and chemical properties of an API without compromising its structure and bioactivity.5 Co-crystals are multi-component assemblies held together by freely reversible, non-covalent interactions (Figure 2).

While it appears there are no co-crystal drugs currently on the market, the ability to leverage this type of polymorph to improve parameters such as solubility and stability has obvious appeal. In light of this, API co-crystals are being evaluated alongside other solid forms during the polymorph screen with increased frequency.

Because such a large number of co-crystal “formers” are available, the range of API co-crystals that can be created is nearly limitless, offering a potentially broad patent space and additional opportunities for lifecycle management.

References

1 Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, 2002.

2 Bauer, J., Spanton, S., Henry, R., Quick, J., Dziki, W., Porter, W., and Morris, J. Ritonavir: an extraordinary example of conformational polymorphism. Pharmaceutical Research. 2001. 18(6) 859-866.

3 Bernstein, J. Polymoprhisms and patents from a chemist’s point of view. 2004. Accessed at http://erice2004.docking.org/vcourse/ polymorph/19sat/1000-Bernstein/Bernstein.ppt

4 Blurred Vision. The Economist, May 29, 1993: Page 86.

5 Schultheiss, N. and Newman, A.Pharmaceutical Cocrystals and their physicochemical properties. Crystals Growth and Design.2009.9(6):2950-2967.

Jan-Olav Henck, Ph.D. is a site director for Aptuit, a global provider of integrated pharmaceutical services. He can be reached at jan-olav.henck@aptuit.com. Stephen R. Bryn is the Charles B. Jordan Professor of Medicinal Chemistry at Purdue University.He can be reached at sbryn@purdue.edu.