In Search of an Optimal Solid Form - Pharmaceutical Technology

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In Search of an Optimal Solid Form
The solid form of an API plays a crucial role in drug quality, and advancing methods for screening, detection, and characterization is key.


Pharmaceutical Technology
Volume 35, Issue 7, pp. 44-48

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.


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