Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate

Abstract

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.

Remarkable Similarity of Molecular Packing in Crystals of Racemic and Enantiopure 2-Phenylpropionamide: Z′ = 4 Structures, Molecular Disorder, and the Formation of a Partial Solid Solution

“…The calculated crystal shapes agree with experimental observations (Figure ); one can see that the most developed faces are parallel to the layers of H-bonded molecules of 2PPA. Recent studies , demonstrate the importance of crystal habit in the dissolution rate of pharmaceuticals.…”

Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time

“…The few studies on peptide crystallization were mostly aimed at crystal structure determination [14][15][16], where method such as vapor diffusion was used to prepare large crystals for good diffraction quality [14]. On the other hand, in addition to crystal size, crystal habit (or external shape), as one of the quality attributes, can affect the active pharmaceutical ingredient (API) in the properties (e.g., filterability [17]) that can ultimately influence the downstream processing efficiency [18]. Additionally, crystal habit has been found to influence the bioavailability of the pharmaceuticals by affecting the solubility and dissolution [19,20].…”

“…2) The difference of specific area in O and SAN crystals of Van might affect their dissolution profiles of on the pharmacokinetics behaviors, which ultimately affect the bioavailability of the API [18,19]. Therefore, it is worth to investigate pharmacokinetics behaviors of these two crystal habits.…”

“…These properties greatly influence the downstream processing efficiencies in steps such as filtration, centrifugation, drying, tableting, as well as storage and handling [17]. Moreover, crystal habit also influences the solubility, dissolution, and consequently the bioavailability and therapeutic activity of pharmaceuticals/biologics [18,19,256,257].…”

Advanced strategies to enhance the performances of crystallization and precipitation of biopharmaceuticals

“…The few studies on peptide crystallization were mostly aimed at crystal structure determination [14][15][16], where method such as vapor diffusion was used to prepare large crystals for good diffraction quality [14]. On the other hand, in addition to crystal size, crystal habit (or external shape), as one of the quality attributes, can affect the active pharmaceutical ingredient (API) in the properties (e.g., filterability [17]) that can ultimately influence the downstream processing efficiency [18]. Additionally, crystal habit has been found to influence the bioavailability of the pharmaceuticals by affecting the solubility and dissolution [19,20].…”