Jun-Bom Park

Development of an antifungal denture adhesive film for oral candidiasis utilizing hot melt extrusion technology.

Objectives: The overall goal of this research was to produce a stable hot-melt extruded ‘Antifungal Denture Adhesive film’ (ADA) system for the treatment of oral candidiasis. Methods: The ADA systems with hydroxypropyl cellulose (HPC) and/or polyethylene oxide (PEO) containing clotrimazole (10%) or nystatin (10%) were extruded utilizing a lab scale twin-screw hot-melt extruder. Rolls of the antifungal-containing films were collected and subsequently die-cut into shapes adapted for a maxillary (upper) and mandibular (lower) denture. Results: Differential scanning calorimeter and powder X-ray diffraction results indicated that the crystallinity of both APIs was changed to amorphous phase after hot-melt extrusion. The ADA system, containing blends of HPC and PEO, enhanced the effectiveness of the antimicrobials a maximum of fivefold toward the inhibition of cell adherence of Candida albicans to mammalian cells/Vero cells. Remarkably, a combination of the two polymers without drug also demonstrated a 38% decrease in cell adhesion to the fungi due to the viscosity and the flexibility of the polymers. Drug-release profiles indicated that both drug concentrations were above the minimum inhibitory concentration (MIC) for C. albicans within 10 min and was maintained for over 10 h. In addition, based on the IC50 and MIC values, it was observed that the antifungal activities of both drugs were increased significantly in the ADA systems. Conclusions: Based on these findings, the ADA system may be used for primary, prophylaxis or adjunct treatment of oral or pharyngeal candidiasis via controlled release of the antifungal agent from the polymer matrix.

Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF.

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug. Hot-melt extrusion (HME) processing was used to prepare solid dispersions utilizing blends of polymers. Drug loading showed a significant effect on the dissolution rate of CBZ in all of the tested ratios of Soluplus® and HPMCAS-HF. CBZ was completely miscible in the polymeric blends of Soluplus® and HPMCAS-HF up to 40% drug loading. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and dissolution studies. DSC and XRD data confirmed the formation of amorphous solid dispersions of CBZ in the polymeric blends of Soluplus® and HPMCAS-HF. Drug loading and release of CBZ was increased with Soluplus® (when used as the primary matrix polymer) when formulations contained Soluplus® with 7–21% (w/w) HPMCAS-HF. In addition, this blend of polymers was found to be physically and chemically stable at 40°C, 75% RH over 12 months without any dissolution rate changes.

New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method.

The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The aim of this study was to prepare uniformly and homogeneously distributed dosage forms of very low-dose drugs using twin screw hot-melt extrusion (HME) and to investigate the distribution of drugs using instrumental analyses. For the feasibility of HME method, a very low amount of coumarin-6, a fluorescent dye, was used to visualize distribution images using confocal laser scanning microscope (CLSM). Limaprost, tamsulosin and glimepiride were then used as low-dose model drugs to study the applicability of HME for content uniformity and distribution behaviors. Hydrophilic thermosensitive polymers with low melting point, such as Poloxamer188 and polyethylene glycol (PEG) 6000, were chosen as carriers. The melt extrusion was carried out around 50°C, at which both carriers were easily dissolved but model drugs remained in solid form. The physicochemical properties of the hot-melt extrudates, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were measured. Content uniformity of the drugs was also checked by HPLC. CLSM imaging showed that model drugs were well distributed throughout the hot-melt extrudate, giving better content uniformity with low batch-to-batch variations compared with simple physical mixtures. DSC, PXRD and FT-IR data showed that there was no interaction or interference between model drugs and thermosensitive polymers. The current HME methods could be used to prepare uniformly distributed and reproducible solid dosage forms containing very low dose drugs for further pharmaceutical applications.

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations.

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

The Effects of Screw Configuration and Polymeric Carriers on Hot-Melt Extruded Taste-Masked Formulations Incorporated into Orally Disintegrating Tablets

The primary aim of this research was to produce successfully taste masked formulations of Sildenafil Citrate (SC) using hot-melt extrusion (HME) technology. Multiple screw configurations and polymeric carriers were evaluated for their effects on taste masking efficiency, which was assessed by both E-tongue analysis and in vitro dissolution in simulated salivary fluid (SSF, pH 6.8 artificial saliva). The screw configurations were further assessed for their effects on the morphology of the API using PXRD, FT-IR and mid-infrared chemical imaging. It was determined that the screw configuration had a profound effect on the taste masking efficiency of the formulations as a result of altering the physical state of the API. Selected extruded formulations using ethylcellulose (EC) with a pore former were further formulated into orally disintegrating tablets (ODTs), which were optimized by varying the grade and percentage of the superdisintegrant used. An optimized disintegration time of approximately 8 seconds was achieved. The final ODT formulation exhibited excellent taste masking properties with over 85% drug release in gastric media as well as physical tablet properties. Interestingly, friability, which tends to be a common concern when formulating ODTs, was well within the acceptable limits (<1%) for common tablets.

Investigation of physicochemical factors affecting the stability of a pH-modulated solid dispersion and a tablet during storage

The stability of solid dispersions (SD) during storage is of concern. We prepared the pH-modulated SD (pSD) and compressed tablets consisting of polyethylene glycol (PEG) 6000 as a carrier, drug and MgO (alkalizer). Telmisartan (TEL), an ionizable poorly water-soluble drug, was chosen as a model drug. The changes in physicochemical factors such as the dissolution rate, drug crystallinity, microenvironmental pH (pH(M)) and intermolecular interactions of the pSD and the tablets were investigated over 3 months under different temperature and relative humidity (RH) conditions: refrigerator (5-8 °C), 25 °C/32% RH, 25 °C/55% RH, 25 °C/75% RH, 40°C/32% RH, 40 °C/55% RH, and 40 °C/75% RH. Differential scanning calorimetry (DSC) analysis of all samples revealed no distinct changes in the drug melting point. In contrast, powder X-ray diffraction (PXRD) diffractograms revealed that samples stored at 40 °C/75% RH for 1 month, 25 °C/75% RH for 3 months and 40 °C at all humidity conditions for 3 months showed gradual recrystallization of the drug. Fourier transform infrared (FTIR) spectra indicated a reduced intensity of intermolecular interactions between TEL and MgO in the pSD and tablet. The pH(M) also gradually decreased. These altered physicochemical factors under the stressed conditions resulted in decreased dissolution profiles in intestinal fluid (pH 6.8). In contrast, the dissolution rate in gastric fluid (pH 1.2) was almost unchanged because of the high intrinsic solubility of TEL at this pH.

Effects of solvents and crystallization conditions on the polymorphic behaviors and dissolution rates of valsartan

For the quality evaluation of raw materials, the influence of various types of solvents on the polymorphic crystallization behaviors and dissolution rates of two sources of valsartan (VAL) from China and India was investigated. Samples were prepared by recrystallization from water or organic solvents, such as acetonitrile, acetone and ethanol, using methods with and without heating. Recrystallization behaviors were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Scanning electron microscopy (SEM) was also used to observe the morphology of samples. The dissolution rate of recrystallized samples in water was evaluated and compared to the original VAL sample. There were significant differences in morphology, crystal structure and dissolution rate among the samples recrystallized using organic solvents. VAL was transformed into another polymorphic form by the solvents and recrystallization conditions. These physical properties of VAL also differed between the two sources of VAL. Thus, the physicochemical differences of raw materials should be carefully considered in early dosage formulation approaches.

Influence of pressurized carbon dioxide on ketoprofen-incorporated hot-melt extruded low molecular weight hydroxypropylcellulose

Abstract Objectives: The aim of the current research project was to investigate the effect of pressurized carbon dioxide (P-CO2) on the physico-mechanical properties of ketoprofen (KTP)-incorporated hydroxypropylcellulose (HPC) (Klucel™ ELF, EF, and LF) produced using hot-melt extrusion (HME) techniques and to assess the plasticization effect of P-CO2 on the various polymers tested. Methods: The physico-mechanical properties of extrudates with and without injection of P-CO2 were examined and compared with extrudates with the addition of 5% liquid plasticizer of propylene glycol (PG). The extrudates were milled and compressed into tablets. Tablet characteristics of the extrudates with and without injection of P-CO2 were evaluated. Results and conclusion: P-CO2 acted as a plasticizer for tested polymers, which allowed for the reduction in extrusion processing temperature. The microscopic morphology of the extrudates was changed to a foam-like structure due to the expansion of the CO2 at the extrusion die. The foamy extrudates demonstrated enhanced KTP release compared with the extrudates processed without P-CO2 due to the increase of porosity and surface area of those extrudates. Furthermore, the hardness of the tablets prepared by foamy extrudates was increased and the percent friability was decreased. Thus, the good binding properties and compressibility of the extrudates were positively influenced by utilizing P-CO2 processing.

Advances in hot-melt extrusion technology toward pharmaceutical objectives

Hot Melt Extrusion (HME) technology is a widely used for manufacturing process in the plastic and pharmaceutical industries and is an efficient and simple for the production of a solid dispersion. This technique is an environmental friendly, continuous process that does not use solvents. It is time and cost efficient and can be easily scaled up. In addition, HME may be used in conjunction with other technologies to effectively increase the solubility and dissolution rate of poorly water-soluble drugs. Numerous research papers on the progress of HME technology in the pharmaceutical industry have been written, and products manufactured using HME have been approved by the FDA. However, there are some drawbacks to the products manufactured using through HME. These are related to the high energy input coming from the applied shear forces and high temperature, which could lead to drug or polymer degradation and thus significantly impact the product quality. Despite these disadvantages, HME has been employed in various advanced applications, such as taste masking and targeted drug delivery. This review article focuses on advances in HME technology, which include improvement in the weaknesses of HME, patient-centric formulations, and the outlook for uses such as formulation development.

Evaluation of the recrystallization kinetics of hot-melt extruded polymeric solid dispersions using an improved Avrami equation

Abstract The recrystallization of an amorphous drug in a solid dispersion system could lead to a loss in the drug solubility and bioavailability. The primary objective of the current research was to use an improved kinetic model to evaluate the recrystallization kinetics of amorphous structures and to further understand the factors influencing the physical stability of amorphous solid dispersions. Amorphous solid dispersions of fenofibrate with different molecular weights of hydroxypropylcellulose, HPC (Klucel™ LF, EF, ELF) were prepared utilizing hot-melt extrusion technology. Differential scanning calorimetry was utilized to quantitatively analyze the extent of recrystallization in the samples stored at different temperatures and relative humidity (RH) conditions. The experimental data were fitted into the improved kinetics model of a modified Avrami equation to calculate the recrystallization rate constants. Klucel LF, the largest molecular weight among the HPCs used, demonstrated the greatest inhibition of fenofibrate recrystallization. Additionally, the recrystallization rate (k) decreased with increasing polymer content, however exponentially increased with higher temperature. Also k increased linearly rather than exponentially over the range of RH studied.