Poor biopharmaceutical performance of Biopharmaceutical Classification System (BCS) class II drug molecules is a major hurdle in the design and development of pharmaceutical formulations. Anisotropic surface chemistry of different facets in crystalline material affects physicochemical properties, such as wettability, of drugs. In the present investigation, a molecule-centered approach is presented toward crystal habit modification of celecoxib (CEL) and its effect on oral bioavailability. Two crystal habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal habit (CEL-P), were obtained by recrystallization from toluene at 25 and 60 °C, respectively. Compared to CEL-A, CEL-P exhibited significantly faster dissolution kinetics in aqueous media and significantly higher C max and shorter T max in an oral bioavailability study. The significant enhancement in dissolution and biopharmaceutical performance of CEL-P was attributed to its more abundant hydrophilic surfaces compared to CEL-A. This conclusion was supported by wettability and surface free energy determination from contact angle measurements and surface chemistry determination by X-ray photoelectron spectroscopy (XPS), crystal structure modeling, and crystal face indexation.

In the present study, the role of α-relaxation toward isothermal crystallization of amorphous celecoxib was studied using dielectric spectroscopy (DES). The dielectric response of the α-relaxation was measured as a function of frequency (10⁻¹ to 10⁶ Hz), isothermally at every 4 K interval in the range of 303.15 to 443.15 K. The dielectric loss spectrum at each temperature was analyzed using the Havriliak Negami (HN) equation to extract the characteristic relaxation time, τ(HN). Two Vogel-Fulcher-Tammann (VFT) functions were required for representing the temperature dependence of τ(HN) across the temperature range of study. The VFT fit parameters obtained from the two regions varied drastically pointing toward the underlying differences in the dynamics of relaxation above and below the crossover. Later, in situ isothermal crystallization experiments were performed at 363.15, 368.15, 373.15, and 378.15 K. The conversion rate, obtained from the normalized dielectric strength, was modeled using the Avrami model, which indicated the possibility of different crystallization mechanism at higher crystallization temperatures. HN shape parameters, α(HN) and product of α(HN) and β(HN), were analyzed during the course of crystallization to understand the dynamics of amorphous phase when crystallites were being evolved. HN shape parameters indicated α-like motions were affected, whereas β-like remained unaffected by the crystallization temperature. Characteristic crystallization time, τ(cr), obtained from Avrami fits, showed Arrhenius type of temperature dependence (R² = 0.999). A plot between log τ(cr) and log τ(HN) show a linear regression with R² of 0.997 indicating the direct correlation between these two phenomena. However, the coupling coefficient was found to be varying within the temperature range of study, indicating tendency of crystallization to be more diffusion controlled at higher crystallization temperatures. With different crystalline solid phase crystallizing at higher crystallization temperature, complemented with direct correlation between log τ(cr) and log τ(HN), Avrami modeling of crystallization and HN shape parameter analysis, the role of α-relaxation in the crystallization of amorphous celecoxib at T > T(g) is emphasized.

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Intrinsic dissolution rate (IDR) is a useful technique to differentiate the solid forms of a drug. In the present study, the impact of crystal habit and crystal size on IDR of celecoxib (CEL) in different media was assessed. The IDR of plate-shaped CEL crystals (CEL-P) (53.4 ± 6.7 μg/min/cm2) was 46.3% higher than that of acicular crystals (CEL-A) (36.5 ± 1.7 μg/min/cm2) in pH 12 phosphate buffer. Contact angle experiments and values of dispersive and polar components of surface free energy indicated better wettability of CEL-P compacts than CEL-A. Higher IDR and better wettability of CEL-P were attributed to favorable exposure of hydrophilic crystal facets on compact surface, due to preferred orientation during compaction. In contrast to native samples, milled CEL-A (MCEL-A) and milled CEL-P (MCEL-P) showed similar IDR. Interestingly, IDR of CEL-A (36.5 ± 1.7 μg/min/cm2) and MCEL-A (35.64 ± 5.09 μg/min/cm2) did not show any significant difference (p > 0.05). However, IDR of CEL-P (53.4 ± 6.7 μg/min/cm2) was significantly higher (p < 0.05) than that of MCEL-P (39.15 ± 2.48 μg/min/cm2). This was ascribed to (i) differential cleavage behavior of CEL-A and CEL-P during milling and (ii) reduced degree of preferred orientation of hydrophilic facets in MCEL-P compacts. This work provides an interesting case study of the impact of particle level properties and surface molecular environment on IDR.

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