Microscopic Cracks Modulate Nucleation and Solid-State Crystallization Tendency of Amorphous Celecoxib.

Drugs have been classified as fast, moderate, and poor crystallizers based on their inherent solid-state crystallization tendency. Differential scanning calorimetry-based heat-cool-heat protocol serves as a valuable tool to define the solid-state crystallization tendency. This classification helps in the development of strategies for stabilizing amorphous drugs. However, microscopic characteristics of the samples were generally overlooked during these experiments. In the present study, we evaluated the influence of microscopic cracks on the crystallization tendency of a poorly water-soluble model drug, celecoxib. Cracks developed in the temperature range of 0-10 °C during the cooling cycle triggered the subsequent crystallization of the amorphous phase. Nanoindentation study suggested minimal differences in mechanical properties between samples, although the cracked sample showed relatively inhomogeneous mechanical properties. Nuclei nourishment experiments suggested crack-assisted nucleation, which was supported by Raman data that revealed subtle changes in intermolecular interactions between cracked and uncracked samples. Celecoxib has been generally classified as class II, i.e., a drug with moderate crystallization tendency. Interestingly, classification of amorphous celecoxib may change depending on the presence or absence of cracks in the amorphous sample. Hence, subtle events such as microscopic cracks should be given due consideration while defining the solid-state crystallization tendency of drugs.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150 g/h), extruder screw speed (150-300 rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25 µm from ~80 µm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650 g/h), lower extruder screw speed (150 rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems.

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.

Analytical and Computational Methods for the Determination of Drug-Polymer Solubility and Miscibility.

In the pharmaceutical industry, poorly water-soluble drugs require enabling technologies to increase apparent solubility in the biological environment. Amorphous solid dispersion (ASD) has emerged as an attractive strategy that has been used to market more than 20 oral pharmaceutical products. The amorphous form is inherently unstable and exhibits phase separation and crystallization during shelf life storage. Polymers stabilize the amorphous drug by antiplasticization, reducing molecular mobility, reducing chemical potential of drug, and increasing glass transition temperature in ASD. Here, drug-polymer miscibility is an important contributor to the physical stability of ASDs. The current Review discusses the basics of drug-polymer interactions with the major focus on the methods for the evaluation of solubility and miscibility of the drug in the polymer. Methods for the evaluation of drug-polymer solubility and miscibility have been classified as thermal, spectroscopic, microscopic, solid-liquid equilibrium-based, rheological, and computational methods. Thermal methods have been commonly used to determine the solubility of the drug in the polymer, while other methods provide qualitative information about drug-polymer miscibility. Despite advancements, the majority of these methods are still inadequate to provide the value of drug-polymer miscibility at room temperature. There is still a need for methods that can accurately determine drug-polymer miscibility at pharmaceutically relevant temperatures.

Role of solvent in differential phase behavior of celecoxib during spray drying.

Spray drying is an industrially viable technique that can be used for modulation of the physical form of Active Pharmaceutical Ingredients (API), which is governed by inherent crystallization tendency and processing parameters during spray drying. In the current study, we investigated the role of solvent in differential phase behavior of celecoxib, a poor crystallizer, during spray drying and unveiled the underlying mechanisms. 1% w/v solutions of celecoxib in three different compositions of methanol (M)-water (W) solvent system were spray dried using a laboratory spray dryer. The proportions were 0, 5 and 10% v/v of water in methanol (MW0, MW5, and MW10, respectively). Percentage crystallinity of the spray dried products were evaluated using modulated differential scanning calorimetry and was in the order MW10 > MW5 > MW0 (i.e. 18.52% > 8.13% > 0%). Solution-state and solid-state crystallization events responsible for the experimental observations were probed using microscopy, Raman spectroscopy, and non-isothermal crystallization studies. An intermediate amorphous phase was generated for the studied samples, which underwent crystallization under the influence of chamber temperature for MW5 and MW10. Additionally, liquid-liquid phase separation (LLPS) at very high level of supersaturation led to relatively higher crystallinity for MW10. Insights from this work provide the basis for understanding of probable phase behavior of poor crystallizers during spray drying.

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization.

Crystallization is an important and difficult to control unit operation in the pharmaceutical industry. Crystallization can control molecular (i.e., polymorphism) and particulate (i.e., particle size and crystal habit) properties of active pharmaceutical ingredient (API). Moreover, these molecular and particulate properties govern the manufacturability, stability, and biopharmaceutical performance of the API and drug product. Nucleation is a key step and primary heterogeneous nucleation is a common mode of nucleation during crystallization. Hence, it is important to understand the parameters affecting primary heterogeneous nucleation, to achieve desirable properties in crystalline APIs. Primary heterogeneous crystallization has usually been linked to the surface characteristics like topography and functionality of the heteronucleant. The review outlines recent findings in the primary heterogeneous crystallization with specific emphasis on its pharmaceutical applications including regulatory considerations. Molecular-level mechanisms governing heteronucleation and subsequent outcome in terms of molecular as well as particulate-level properties of API have also been discussed. Moreover, general guidance for the selection of heteronucleant has also been included. Heterogeneous crystallization is a promising tool for efficient crystallization of API having properties for optimal pharmaceutical performance.

Role of Surface Characteristics of Mannitol in Crystallization of Fenofibrate During Spray Drying.

NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients. Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-assisted phenomenon and surface characteristics of mannitol were hypothesized to play important role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on 2 surfaces of mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in the presence of rougher surface (tind < 1 min) compared with smooth surface (tind = 49.28 min). This was attributed to higher porosity (75%) and surface polarity (~1.25-fold) of rough surface as compared with smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate. These findings can be utilized for generating crystalline solid dispersions using spray drying in the presence of mannitol. The crystalline solid dispersions can be used for the development of oral solid dosage forms.

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling.

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.