Changquan Calvin Sun

Characterization of thermal behavior of deep eutectic solvents and their potential as drug solubilization vehicles.

Deep eutectic solvent (DES) is a new class of solvents typically formed by mixing choline chloride with hydrogen bond donors such as amines, acids, and alcohols. Most DESs are non-reactive with water, biodegradable, and have acceptable toxicity profiles. Urea-choline chloride and malonic acid-choline chloride eutectic systems were characterized using differential scanning calorimetry (DSC) and thermal microscopy. A potential new 2:1 urea-choline chloride cocrystal with a melting point of 25 degrees C was characterized at the eutectic composition. The formation of this cocrystal suggests that DES should not be universally explained by simple eutectic melting, and may be useful in guiding the search for new DES systems. The lack of nucleation of the malonic acid-choline chloride system prohibited the construction of a phase diagram for this system using DSC. We also investigated possible uses of DES in solubilizing poorly soluble compounds for enhanced bioavailability in early drug development such as toxicology studies. For five poorly soluble model compounds, solubility in DES is 5 to 22,000 folds more than that in water. Thus, DES can be a promising vehicle for increasing exposure of poorly soluble compounds in preclinical studies.

Materials science tetrahedron—A useful tool for pharmaceutical research and development

The concept of materials science tetrahedron (MST) concisely depicts the inter-dependent relationship among the structure, properties, performance, and processing of a drug. Similar to its role in traditional materials science, MST encompasses the development in the emerging field of pharmaceutical materials science and forms a scientific foundation to the design and development of new drug products. Examples are given to demonstrate the applicability of MST to both pharmaceutical research and product development. It is proposed that a systematic implementation of MST can expedite the transformation of pharmaceutical product development from an art to a science. By following the principle of MST, integration of research among different laboratories can be attained. The pharmaceutical science community as a whole can conduct more efficient, collaborative, and coherent research.

Cocrystallization for successful drug delivery

Introduction: Cocrystallization is an effective crystal engineering approach for modifying the crystal structure and properties of drugs. The number of examples of solving drug formulation and manufacture problems by cocrystallization is rapidly growing. An updated review that systematically examines the cocrystal research in the context of drug delivery is timely and valuable. Areas covered: Topics covered in this review include nature of cocrystal, impact of cocrystallization on key pharmaceutical properties (both enhancement and deterioration), cocrystal preparation method and future directions in this field. The focus of this review is on the crystal engineering and pharmaceutical literature in the last 5 years. However, classical literature is also examined when relevant. Expert opinion: The most effective cocrystal research relies on both in-depth understanding of structure–property relationship and efficient preparation of desired cocrystals. The future cocrystal research will see growth in the areas of designing ternary and higher-order structures, cocrystals between neutral and ionic species, cocrystal polymorphism, cocrystal glasses and thermodynamics of cocrystallization.

Simultaneously Improving the Mechanical Properties, Dissolution Performance, and Hygroscopicity of Ibuprofen and Flurbiprofen by Cocrystallization with Nicotinamide

ABSTRACTPurposeTo be fully exploitable in both formulation and manufacturing, a drug cocrystal needs to demonstrate simultaneous improvement of multiple key pharmaceutical properties over the pure drug crystal. The present work was aimed at investigating such feasibility with two model profen-nicotinamide cocrystals.MethodsPhase pure 1:1 ibuprofen-nicotinamide and flurbiprofen-nicotinamide cocrystals were prepared from solutions through rapid solvent removal using rotary evaporation,and characterized by DSC, PXRD, FTIR, phase solubility measurements, equilibrium moisture sorption analysis, dissolution testing and tabletability analysis.ResultsTemperature-composition phase diagrams constructed from DSC data for each profen and nicotinamide crystal revealed the characteristic melting point of the 1:1 cocrystal as well as the eutectic temperatures and compositions. Both cocrystals exhibited higher intrinsic dissolution rates than the corresponding profens. The cocrystals also sorbed less moisture and displayed considerably better tabletability than the individual profens and nicotinamide.ConclusionsPhase behaviors of 1:1 profen-nicotinamide cocrystal systems were delineated by constructing their temperature-composition phase diagrams. Cocrystallization with nicotinamide can simultaneously improve tableting behavior, hygroscopicity, and dissolution performance of ibuprofen and flurbiprofen. This could pave the way for further development of such cocrystal systems into consistent, stable, efficacious and readily manufacturable drug products.

Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1:1 co-crystal

Theophylline and methyl gallate can form a 1 : 1 co-crystal. Their tableting performance follows the order of theophylline > co-crystal ≫ methyl gallate. While co-crystallization profoundly improves the tabletability of methyl gallate, it significantly deteriorates that of theophylline. This difference in bulk compaction behaviour originates from the dissimilar crystal plasticity and elasticity, which results from unique molecular packing features in the respective crystal lattices. The presence of a three-dimensional hydrogen bonded network gives rise to very low plasticity in the methyl gallate crystal, which leads to its poor tabletability. In contrast, the layers of two-dimensional rigid, hydrogen bonded molecules in the co-crystal improve the crystal plasticity, by facilitating slip with shear that, in turn, enhances tabletability. However, theophylline undergoes plastic deformation more readily when compared to the co-crystal, because the slip layers in theophylline are composed of hydrogen bonded columns, which provide additional flexibility for slip. As a consequence, theophylline crystals have significantly enhanced tabletability.

Quantifying Effects of Particulate Properties on Powder Flow Properties Using a Ring Shear Tester

Effects of particle size, morphology, particle density, and surface silicification, on powder flow properties were investigated using a ring shear tester. Flow properties were quantified by flow function (FF), that is, unconfined yield strength, f(c), as a function of major principal stress. A total of 11 powders from three series of microcrystalline cellulose (MCC): Avicel (regular MCC, elongated particles), Prosolv (silicified MCC, elongated particles), and Celphere (spherical MCC), were studied. Particle size distribution in each type of MCC was systematically different. Within each series, smaller particles always led to poorer powder flow properties. The slope of FF line was correlated to degree of powder consolidation by external stress. A key mechanism of the detrimental effect of particle size reduction on flow properties was the larger powder specific surface area. Flow properties of Celphere were significantly better than Avicel of comparable particles size, suggesting spherical morphology promoted better powder flow properties. Flow properties of powders different in densities but similar in particle size, shape, and surface properties were similar. When corrected for density effect, higher particle density corresponded to better flow behavior. Surface silicification significantly improved flow properties of finer MCC, but did not improve those of coarser.

Development of a high drug load tablet formulation based on assessment of powder manufacturability: Moving towards quality by design

The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of approximately 19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10 g) approaches. Larger batches were subsequently manufactured to confirm predictions.

Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling.

Poor flow properties hinder the easy handling of powders during industrial-scale processing. In this work, we show that powder flow can be substantially improved by reducing the cohesion of powders by coating them with nanosized guest particles. We further show that comilling is an efficient process for nanocoating. We have systematically investigated the effects of total number of comilling cycles (10-70 cycles) and silica loading (0-1.0 wt %) on the flow behavior of a highly cohesive and poorly flowing grade of microcrystalline cellulose powder (Avicel PH105). Optimum flow enhancement has been achieved with 1.0 wt % silica loading at 40 comilling cycles. The flow properties of nanocoated Avicel PH105 are comparable to those of Avicel PH102, which exhibits adequate flowability for processing on a high-speed tablet press. Comilling is fast and suitable for continuous processing. It shows potential for addressing industrial powder handling problems caused by poor powder flow properties.

Ionized form of acetaminophen with improved compaction properties

The most widely used antipyretic and analgesic drug, acetaminophen, has the long standing problem of extremely poor tableting properties and has been considered as non-ionizable. Here we report the synthesis of the first ionized solid-state structure, acetaminophen HCl monohydrate, and demonstrate its excellent tableting properties.

Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound

Powder compaction data of three polymorphic Forms I (shearing), II (bending) and III (brittle) of 6-chloro-2,4-dinitroaniline demonstrates a direct relationship among mechanical properties, crystal structure and tableting behaviour, showing the essence of structure based assessment of mechanical properties of crystals, e.g., for identifying more efficient API formulation and manufacture processes.