Gregory A. Stephenson

Characterization of the solid state: quantitative issues

Quantitative analysis of solid state composition is often used to ensure the safety and efficacy of drug substances or to establish and validate the control of the pharmaceutical production process. There are a number of common techniques that can be applied to quantify the phase composition and numerous different methods for each technique. Each quantitative option presents its own issues in ensuring accuracy and precision of the solid state method. The following article describes many of the common techniques that are used for quantitative phase analysis and many of the considerations that are necessary for the development of such methods.

Physical characterization of polymorphic drugs: an integrated characterization strategy

Abstract The potential impact of changing crystal forms during late-stage drug development, in terms of cost and product delay, justifies systematic and early characterization of polymorphism. A thorough understanding of polymorph characteristics also allows selection of the best form to market. The authors review the key elements of polymorph characterization (identification and quantitation, structures, properties and structure-property relationships). The emphasis is on recent developments and an integrated characterization strategy for different types of polymorphs using crystallographic, spectroscopic, microscopic and thermal techniques.

Physical Stability of Salts of Weak Bases in the Solid-State

When selecting the physical form of an active pharmaceutical substance, there is often a question of when a molecules pKa renders it too low for salt formation and formulation into a product that will be sufficiently physically stable to provide adequate shelf life. In the paper, a graph is provided that tabulates pKa values of active pharmaceuticals versus the salt or free base form that was chosen to be developed as an orally administered drug product. Tabulation of the data provides insight into where, if any, practical cutoff exists, under which salt formation should not be considered. Specific examples of disproportionation reactions are reviewed and are described in light of the concepts of pH maximum, pH microenvironment, and Gibbs free energy to gain further insight into when such reactions become favorable. The driving force for disproportionation reactions is substantially greater than that for polymorphic form conversion, and as a consequence, its probability of occurring in the solid-state is much greater when formulated in favorable microenvironments. Factors that influence the reaction rate are examined. It is concluded that each salt should be evaluated on the merit of its physical properties and often the most soluble salt will not be ones best choice. Unfortunately, compounds that stand to benefit the most from salt formation due to their exceptionally low intrinsic solubility are the ones that will be most likely to disproportionate if their pKa is relatively low.

Outcomes of the International Union of Crystallography Commission on Powder Diffraction Round Robin on Quantitative Phase Analysis: samples 2, 3, 4, synthetic bauxite, natural granodiorite and pharmaceuticals

The International Union of Crystallography (IUCr) Commission on Powder Diffraction (CPD) has sponsored a round robin on the determination of quantitative phase abundance from diffraction data. The aims of the round robin have been detailed by Madsen et al. [J. Appl. Cryst. (2001), 34, 409–426]. In summary, they were (i) to document the methods and strategies commonly employed in quantitative phases analysis (QPA), especially those involving powder diffraction, (ii) to assess levels of accuracy, precision and lower limits of detection, (iii) to identify specific problem areas and develop practical solutions, (iv) to formulate recommended procedures for QPA using diffraction data, and (v) to create a standard set of samples for future reference. The first paper (Madsen et al., 2001) covered the results of sample 1 (a simple three-phase mixture of corundum, fluorite and zincite). The remaining samples used in the round robin covered a wide range of analytical complexity, and presented a series of different problems to the analysts. These problems included preferred orientation (sample 2), the analysis of amorphous content (sample 3), microabsorption (sample 4), complex synthetic and natural mineral suites, along with pharmaceutical mixtures with and without an amorphous component. This paper forms the second part of the round-robin study and reports the results of samples 2 (corundum, fluorite, zincite, brucite), 3 (corundum, fluorite, zincite, silica flour) and 4 (corundum, magnetite, zircon), synthetic bauxite, natural granodiorite and the synthetic pharmaceutical mixtures (mannitol, nizatidine, valine, sucrose, starch). The outcomes of this second part of the round robin support the findings of the initial study. The presence of increased analytical problems within these samples has only served to exacerbate the difficulties experienced by many operators with the sample 1 suite. The major difficulties are caused by lack of operator expertise, which becomes more apparent with these more complex samples. Some of these samples also introduced the requirement for skill and judgement in sample preparation techniques. This second part of the round robin concluded that the greatest physical obstacle to accurate QPA for X-ray based methods is the presence of absorption contrast between phases (microabsorption), which may prove to be insurmountable in some circumstances.

Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine

The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.

Structural relationship and desolvation behavior of cromolyn, cefazolin and fenoprofen sodium hydrates.

The hydrated crystal structures of cromolyn, cefazolin, and fenoprofen sodium salts are reported. The former two compounds are non-stoichiometric hydrates, whereas the fenoprofen lattice maintains its stoichiometry over a broad range of relative humidity. The relationship between composition, lattice parameters, and relative humidity is studied using a combination of moisture sorption isotherms and variable humidity X-ray powder diffraction. The dehydration properties of the sodium salts are related to the ion coordination and hydrogen bonding of the water molecules in the structures. Anisotropic lattice contraction is observed during dehydration of the cromolyn and cefazolin sodium and is related to the closeness of intermolecular contacts in the hydrated structures.

Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation

PurposeSalts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form.MethodsA mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally.Results13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base pKa and solubility of the API.ConclusionsThe model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation.

Structure determination from conventional powder diffraction data: Application to hydrates, hydrochloride salts, and metastable polymorphs

Recent advances in crystallographic computing have made it possible to solve by powder diffraction methods structures that have not been possible to solve by single-crystal methods. Although there is vast improvement in the quality of data obtained from high-intensity synchrotron radiation, we found that surprisingly reliable results can be obtained from conventional laboratory sources. In this article we examine the application of Monte Carlo/simulated annealing methods for the determination of structures ranging in complexity from 9 to 15 degrees of freedom. We re-determine the structures of papaverine hydrochloride and erythromycin A dihydrate by the powder diffraction method and compare the structures to those determined by single-crystal diffraction methods. The structure of a metastable polymorphic form of acetohexamide, form B, is solved and examined spectroscopically. Its structure has not previously been solved by single-crystal techniques because of the small size of its crystals.

Solid-state investigation of the tautomerism of acetohexamide

Polymorphism of the anti-diabetic drug acetohexamide has been investigated by numerous techniques. On the basis of Fourier-transform infrared (FT-IR) data, one of the most common forms, form A, has been proposed to exist in the enol-tautomeric state, whereas form B has been proposed to be in the keto-tautomeric state. The following article examines the solid-state tautomerism of acetohexamide using the techniques of X-ray crystallography and 13 C solid-state nuclear magnetic resonance (NMR) spectroscopy. In the NMR spectra, resonances associated with the acetyl carbonyl and amide carbonyl groups are well resolved. By comparison of the spectra of acetohexamide with those of the related compounds chlorpropamide and tolbutamide, whose crystallographic structures have been determined, it is firmly established that both of the acetohexamide polymorphic forms are in the keto-form. The crystal structure of acetohexamide form A was solved and is reported herein. The structure not only shows the keto-tautomeric state of form A, but also confirms the NMR resonance assignments.

Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors.

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.