In Search of an Optimal Solid Form

The solid form of an active pharmaceutical ingredient (API) influences the drug's solubility, stability, and compatibility with other components in a formulation. API manufacturers are tasked with screening, detecting, and characterizing various physical forms, such as polymorphs, solvates, amorphous materials, and partially disordered materials. Applying solid-state chemistry, however, can be a time-consuming and difficult job, and several recent developments point to ways to facilitate the search for the optimal solid form.

(IMAGE: JASON REED / GETTY IMAGES)

The task at hand

"It is important to apply the most appropriate means of characterizing or identifying all physical forms," says Seenu Srinivasan, PhD, global vice-president and chief scientific officer of CMC pharmaceutical development services at Covance. "On choosing the preferred physical form, a robust crystallization or preparation process needs to be developed, preferably using solvents that are safe, available in large quantities, and are environmentally friendly. Generally, the thermodynamically most stable form is preferred for development. However, in some cases, it may be necessary to progress metastable crystalline forms, solvates, hydrates, or even amorphous materials."

He adds that co-crystals, where more than one molecular entity is incorporated into the crystalline unit cell, can be considered as well. "The latter approach is useful for pharmaceutically engineering the properties of a drug substance when no ionizable moieties are present in the parent molecule," he says. Even when the product is not administered as a solid dose, the physical form of the drug substance should be characterized as fully as possible to ensure that there is no interbatch variability, which may in turn affect, for example, reconstitution time or chemical stability. "We have seen many examples where very subtle variations in physical properties of different batches of an API can have profound effects on its behavior," he says.

Patricia Van Arnum

Decisions to be made

The optimal physical form is based on several factors, which may be influenced by the target product profile, including bioavailability, physical and chemical stability, desired dissolution properties, the impurity profile of the API, drug-substance hygroscopicity, morphology, size distribution, compaction properties, and ability to formulate. "The higher ranking of these criteria for a particular API is used in the decision to choose a free molecule, salt form, or co-crystal," explains Laurent Lafferrere, PhD, head of CMC development services in Porcheville, France, at Covance.

Identifying polymorphs, where a drug substance exists in two or more crystalline phases, is crucial. Polymorph stability is evaluated experimentally by monitoring the phase transition of the different polymorphs in different crystallization media and at different temperatures by using in-situ monitoring probes and analytical solid-state methods, explains Lafferrere. These data are used to manufacture the desired polymorph and to control it through the various manufacturing steps. Polymorphs can undergo phase transitions when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray drying, and compaction. Exposure to environmental conditions, such as humidity and temperature, also can induce polymorph transition. The extent of transition depends on the relative stability of the polymorphs, kinetic barriers to phase transition, and applied stress.

The physical stability of polymorphs may be monotropic or enantiotropic, where the relative thermodynamic stability between the two forms can be inverted with temperature. Additional considerations are made when the physical form of the drug-substance may be modified in the formulation process, such as in hot-melt, lyophilization, solubilization, or suspension in a semisolid matrix, says Lafferrere. Also, drug substance–excipient interactions are considered when stabilizing particular physical and other process parameters that may affect the performance or quality of the final product.

Screening and characterization

Screening protocols involve recrystallization from a diverse array of solvents under thermodynamically and kinetically controlled conditions, explains Steven Byard, PhD, head of physical and molecular characterization at Alnwick, United Kingdom, at Covance. The transformation of metastable states and extended solvent-based studies conducted under a range of crystallization conditions, such different concentrations, temperatures, cooling rates, and stirring rates, are examined. The effect of different impurity profiles and seeding experiments are further considered.

"Of course, one should never forget that one of the principal criteria for recrystallization may be to obtain a desired target purity, with control over both the impurity profile and residual solvents, in addition to obtaining a defined physical quality. Under some circumstances, we apply controlled stress to the API in a variety of carefully chosen matrices to afford physical forms not normally readily obtained by other means," says Byard.

As development progresses to Phases II and III, there is an increased emphasis on the most appropriate crystal morphology, crystal quality, and crystal-size distribution for the commercial formulation and also definition of specifications for the physical quality of API, explains Byard. Verification that the correct polymorph will be retained in later stages of drug-product development is completed by performing a new polymorph screening with a batch of API from the final commercial synthesis route. The critical manufacturing process variables and their ranges are determined and controlled to produce a robust API process that meets established quality attributes.

Screening for physical forms takes into account properties of the molecular structure and explores the effects of solvents, temperature, concentration and various other parameters that can influence crystallization, explains Byard. Many solid forms are generated by the different crystallization approaches, based on the effect of the interfacial energy between the nucleus and the crystallization media, supersaturation (a driving force of crystallization), and temperature. The crystallization methods can be broadly classified into four groups: crystallization by sublimation, melt crystallization, crystallization by spray drying, and crystallization from solution, which is the most commonly used method because it provides data for the crystallization process development. High-throughput screening methods can be used to cover a wide range of conditions to help ensure that all different forms are recognized.

Many complementary techniques exist for characterizing solid forms, such as single crystal X-ray diffraction, X-ray powder diffraction, solid-state nuclear magnetic resonance (SSNMR), infrared spectroscopy, Raman spectroscopy, Terahertz spectroscopy, hot-stage optical microscopy, and thermal analyses. These methods are routinely used and provide the platforms for incremental improvements.

Recent advances

SSNMR probes samples directly at the molecular level to provide information about structure and mobility. Consequently, the physical form of constituents in either physical or chemical mixtures can be examined with relative ease. "This makes SSNMR a technique of choice for studying drug products, where the physical form of the active can be determined in a complex matrix, even if multiple components are amorphous," says Srinivasan. For example, the presence of physical impurities can be determined when lattice modifications are not altered significantly and, by implication, not readily detected by X-ray powder diffraction (1). In another example, researchers at GlaxoSmithKline reported on SSNMR experiments based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of amorphous solid dispersions (2).

NMR crystallography, which incorporates density functional theory calculations, is used to provide molecular-level information about structure and dynamics of drug substances, including solvate characteristics (3, 4). Recently, X-ray photoelectron spectroscopy (XPS), in conjunction with SSNMR and density functional theory prediction, was used to determine co-crystal formation (5, 6). "This too is a promising approach to understanding exactly what is happening at the molecular level and, by implication, enabling a sound basis for making decisions about formulation processes," says Srinivasan.

Surface properties and the related methods for characterization also are important considerations. Researchers at the University of Manchester and Sanofi recently reported on using a surface-sensitive technique, XPS, in detecting the free-base surface enrichment of a pharmaceutical fumarate salt . They reported that a yellow discoloration was observed at the surface of normally white crystals of the fumarate salt, which was preliminary attributed to the presence of trace amounts of free base. The samples with yellow surfaces could not be successfully milled, which was an important part of the production process for providing material of the required physical quality for product formulation. Because no conventional bulk analytical technique could readily provide an explanation for the yellow color, the researchers used XPS to characterize the salt. The identification of residual free base at the surface of the crystalline material by XPS was significant for optimizing the crystallization process to yield material of required quality for milling at the plant scale (7).

Crystal-structure prediction is an active area of research. "Ab initio crystal structure prediction is another promising area as is elucidating hydrogen bonding potential to provide information about the possibility of discovering additional polymorphic forms of a drug substance," says Srinivasan.

Other approaches

Researchers at the University of Missouri recently reported on a new method for converting drugs from one crystalline form to another by applying gas-induced transformations of the antibiotic clarithromycin and lansoprazole, the API in the gastrointestinal drug Prevacid.

For clarithromycin, the researchers converted the kinetic solvent and guest-free crystal forms to the commercially thermodynamically stable polymorph with a reduction in energy costs relative to other commonly used methods. Typical methods involve desolvation of the initial form to a second form, which is heated for 18 h at 110 °C to finally produce the desired polymorph. In the gas-induced process, the clarithromycin crystals were pressurized with carbon dioxide at 350 psi for direct conversion of the initial form to the final thermodynamically stable form in 4 h. For lansoprazole, the researchers also used carbon dioxide to convert the ethanol hydrate of lansoprazole to the solvent-free form that is used commercially. This process improved the approach used in synthesizing lansoprazole, which involves a solvate that readily decomposes and is stirred in water, filtered, and dried intensively (8, 9).

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.

References

1. S.J. Byard et al., J. Pharm. Sci. 94 (6), 1321– 1335 (2005).

2. T.N. Pham et al., Mol. Pharm. 7 (5), 1667–1691 (2010).

3. NMR Crysallography, R. Harris, R.E. Wasylisher, and M.J. Duer, Eds. (John Wiley & Sons, Chichester, UK, 2009).

4. S.M. Reutzell-Edens, "NMR Crystallography and the Elucidation of Structure–Property Relationships in Crystalline Solids," in Engineering of Crystalline Materials Properties, NATO Science for Peace and Security Series B: Physics and Biophysics, J. Novoa, D. Braga, and L. Addadi Eds (Springer, Dordrecht, The Netherlands, 2008), pp. 351–374.

5. J.S. Stevens, S.J. Byard, and S.L.M. Schroeder, J. Pharm. Sci. 99 (11), 4453–4457 (2010).

6. J. S. Stevens et al., J. Phys. Chem. B. 114 (44) 13961–13969 (2010).

7. J.S. Stevens et al., J. Pharm. Sci.100 (3) 942– 948 (2011).

8. J. Tian, S.J. Dalgarno, and J.L. Atwood, J. Am. Chem. Soc. 133 (5), 1399–1404 (2011).

9. C. Arnaud, Chem. & Eng News 89 (3), 8 (2011).