Current Pharmaceutical Design - Volume 22, Issue 32, 2016

Understanding the properties, stability and transformations of the solid-state forms of an active pharmaceutical ingredient (API) in the development pipeline is of crucial importance for process-development, formulation development and FDA approval. Investigation of the polymorphism and polymorphic stability is a routine part of the preformulation studies. Vibrational spectroscopy allows the real-time in situ monitoring of phase transformations and probes intermolecular interactions between API molecules, between API and polymer in amorphous solid dispersions or between API and coformer in cocrystals or coamorphous systems and thus plays a major role in efforts to gain a predictive understanding of the relative stability of solid-state forms and formulations. Infrared (IR), near-infrared (NIR) and Raman spectroscopies, alone or in combination with other analytical methods, are important tools for studying transformations between different crystalline forms, between the crystalline and amorphous form, between hydrate and anhydrous form and for investigating solid-state cocrystal formation. The development of simple-to-use and cost-effective instruments on the one hand and recent technological advances such as access to the low-frequency Raman range down to 5 cm-1, on the other, have led to an exponential growth of the literature in the field. This review discusses the application of IR, NIR and Raman spectroscopies in the study of solid-state transformations with a focus on the literature published over the last eight years.

The importance of using the Raman imaging technique is increasing in pharmaceutical sciences, particularly in the quality control of active pharmaceutical ingredients, formulation design, and manufacturing development. Formulation design based on Raman imaging data is important for achieving quality by design. Recently, several novel Raman imaging measurement and analytical techniques have been reported. It is undoubtedly essential for pharmaceutical researchers and manufacturing engineers to use modern Raman imaging technology to produce the best quality pharmaceutical products. This short review seeks to inform researchers and engineers about recent developments in Raman imaging techniques applicable to formulation design and manufacturing.

Active pharmaceutical ingredients (APIs) can exist in various types of crystalline forms including polymorphs and cocrystals. These multiple crystalline forms of APIs have district physical and physicochemical characteristics. Vibrational spectroscopic techniques used in solid-state pharmaceutical analysis include mid-infrared, Raman and terahertz spectroscopy. In this review, we will focus on the recent vibrational spectroscopic investigation on the polymorphism and cocrystallization of APIs in pharmaceutical fields. The distinctive spectral and structural information of pharmaceutical polymorphs and cocrystals could be obtained based on these vibrational spectroscopic techniques.

A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria.

Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route. Nevertheless, a multitude of potentially clinically important drugs will not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. The aim of this review is to present an overview of properties, formulation, excipients and characterization of solid dispersions corresponding to one of the different formulation strategies for design and development of poorly soluble drugs. This work will review and compare in detail the evolution of solid dispersions focused on the different methods of formulation and production of solid dispersions, their stability, their release properties, their pharmacokinetics and methods for their physicochemical characterization.

Drugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest.

Active pharmaceutical ingredients (APIs) can exist in different polymorphic forms as well as in amorphous state. Polymorphic and amorphous forms of APIs can differ in physicochemical properties which in turn can significantly influence their therapeutic safety and effectiveness of the treatment. This review focuses on benefits and limitations of polymorphic and amorphous forms of APIs used in preformulation and formulation studies. Authors present their work on safety precautions for the use of polymorphic and amorphous forms of APIs, analytical techniques used for their identification as well as methods of their preparation especially in regard to limitations of labile APIs.

For the formation of a drug, a pharmacologically active compound must be prepared in a specific form. The drug must be manufactured, packaged, stored, transported, administred and delivered to a target in the body. To successfully prepare a drug form that will be robust through manufacturing, stable before administration and active with high bioavailability after administration, one needs to produce solid forms with controlled crystal structure and particle size and shape - often as multi-component composites. Considering drugs as materials, one can apply the knowledge of solid-state chemistry and materials science and non-ambient conditions to obtain solid forms with optimized properties. These conditions include, among others, different types of mechanical and ultrasonic treatment, hydrostatic compression, high-temperature or cryogenic spray-drying and crystallization from supercritical solvents. Solid-state reactions (e.g. dehydration or clathrate decomposition) can be effective in accessing metastable polymorphs or in micronizing a sample uniformly. To achieve control over the drug forms and the processes used for their robust manufacturing, one needs to take into account both the thermodynamic and kinetic aspects of their transformations.

Solid-state mechanochemical grinding is important for promoting cocrystal formation, particularly in the design of new solids in the pharmaceutical industry. Pharmaceutical cocrystals are defined as crystalline materials comprising an active pharmaceutical ingredient (API) and one or more appropriate coformers in a definite stoichiometric ratio, formed via non-covalent interactions. Recently, both the US FDA (2013) and the EU EMA (2015) provided a Guidance for Industry and a Reflection Paper, respectively, emphasizing that cocrystals are a new type of substance with potential applications in the pharmaceutical industry. This paper contains a brief and systematic overview of pharmaceutical cocrystals prepared by four grinding processes: neat grinding, solvent-assisted grinding, thermal stress after neat grinding, and polymer-assisted grinding. The paper also highlights some examples of pharmaceutical cocrystals prepared by the above grinding approaches, and discusses the stability of cocrystals prepared by mechanical grinding. Also, an overview of cocrystals that are commercially available or undergoing clinical trials is given. A novel methodology for real-time and in situ monitoring of mechanochemical grinding reactions using various analytical techniques is addressed and can be expected to be applied in the near future.

Stability of a dosage form is its ability to preserve its quality attributes within preset limits. The time span over which these attributes remain within specifications is the shelf-life of the drug product. Stability is a very complex feature and is influenced not only by the stability of the drug substance but also by the stability of excipients and the interaction of the components within the system. Another important contributing factor is the packaging material, which is responsible for the protection of the drug product. Not only drug substances, but also excipients are susceptible to different degradation mechanisms. Amorphous polymers, a relatively frequently used group of excipients, are especially prone to physical instability. Through the process of physical ageing, a slow volume and enthalpy relaxation can be experienced, which can lead to remarkable alterations in solid dosage form properties. Functional changes within the solid dosage form associated with instability include changes in mechanical properties, homogeneity and drug release characteristics, discoloration, phase separation or changes in melting time of suppositories. Stability assessment is a crucial issue during formulation development, which is strictly regulated by authorities responsible for drug registration. The primary purpose of this paper is to give an overview of the different types of physical changes influencing solid state stability of dosage forms, and how such changes can be monitored. We will also illustrate how the quality of a solid dosage form varies with time under the influence of different environmental factors.

The antiepileptic activity of α-substituted acetamides, lactams, and cyclic imides has been known for over six decades. We recently proposed an α-substituted amide group as the minimum pharmacophore responsible for inhibition of neuronal nicotinic acetylcholine receptors by these compounds, with the implication that inhibition of these receptors in the brain might be the unifying mechanism of action for these classes of antiepileptic drugs. In order to realize the pharmacological potential of these orally administered drugs, the relevant aspects of solid-state chemistry and pharmaceutics (including solubility and stability) need to be addressed. A better - more cohesive and generalized - understanding of the solid-state properties of these drugs would pave the road for a rational approach to their development, formulation, and manufacturing. In this paper, Pharmaceutically relevant aspects of the crystal structure and solid-state chemistry of antiepileptic drugs containing the α-substituted amide bond pharmacophore - α-substituted acetamides, lactams, and cyclic imides and the structurally related barbiturates, hydantoins, and acetylureas are reviewed. The applicable experimental and computational approaches are also briefly mentioned.