Quality by Design (QbD) Approach to Develop Colon-Specific Ketoprofen Hot-Melt Extruded Pellets: Impact of Eudragit® S 100 Coating on the In Vitro Drug Release.

BACKGROUND: A pelletizer paired with hot-melt extrusion technology (HME) was used to develop colon-targeted pellets for ketoprofen (KTP). Thermal stability and side effects in the upper gastrointestinal tract made ketoprofen more suitable for this work. METHODS: The pellets were prepared using the enzyme-triggered polymer Pectin LM in the presence of HPMC HME 4M, followed by pH-dependent Eudragit® S 100 coating to accommodate the maximum drug release in the colon by minimizing drug release in the upper gastrointestinal tract (GIT). Box-Behnken Design (BBD) was used for response surface optimization of the proportion of different independent variables like Pectin LM (A), HPMC HME 4M (B), and Eudragit® S 100 (C) required to lower the early drug release in upper GIT and to extend the drug release in the colon. RESULTS: Solid-state characterization studies revealed that ketoprofen was present in a solid solution state in the hot-melt extruded polymer matrix. The desired responses of the prepared optimized KTP pellets obtained by considering the designed space showed 1.20% drug release in 2 h, 3.73% in the first 5 h of the lag period with the help of Eudragit® S 100 coating, and 93.96% in extended release up to 24 h in the colonic region. CONCLUSIONS: Hence, developing Eudragit-coated hot-melt extruded pellets could be a significant method for achieving the colon-specific release of ketoprofen.

Optimization of a Twin screw melt granulation process for fixed dose combination immediate release Tablets: Differential amorphization of one drug and crystalline continuance in the other.

Interest in Twin Screw Melt Granulation (TSMG) processes is rapidly increasing, along with the search for suitable excipients. This study aims to optimize the TSMG process for immediate-release tablets containing two different drugs. The hypothesis is that one poorly water-soluble drug requires amorphous conversion for improved dissolution, while the other water-soluble drug, with a higher melting point (Tm), remains more stable in its crystalline form. Ibuprofen (IBU) and Acetaminophen (APAP) were chosen as the model drug combination to test this hypothesis. Various diluents, binders, and disintegrating agents were assessed for their impact on processability, crystallinity, disintegration, and dissolution during development. The temperatures used during processing were below the Tm of all components, except for IBU. Melted IBU acted as a granulating aid in addition to the binders in the formulation, facilitating granule formation. Physicochemical analyses by Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) confirmed the complete conversion of IBU into an amorphous state and the preserved crystalline nature of APAP. Saturation solubility studies showed an improvement in IBU's solubility by âˆ¼ 32-fold in 0.1 N HCl. Poor tablet disintegration performance led to the addition of disintegrating agents, where osmotic agents (sorbitol and NaCl) were found to significantly enhance disintegration compared to super disintegrants. The optimized formulation showed an enhanced IBU release (∼20 %) compared to the physical mixture (∼12.5) in 0.1 N HCl dissolution studies.

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.

Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness.

Opioid misuse is a public health crisis in the United States. In response, the FDA has approved drug products with abuse-deterrent features to reduce the risk of prescription opioid abuse. Abuse-deterrent formulations (ADFs) typically employ physical or chemical barriers or incorporate agonist-antagonist combinations as mechanisms to deter misuse. This study aims to assess the impact of abuse-deterrent properties, specifically ion-exchange resin complexation as a chemical barrier, on a model drug, promethazine hydrochloride (PMZ) tablets. Various formulations were developed through twin-screw wet granulation (TSWG) followed by twin-screw melt granulation (TSMG). In the TSWG process, the drug interacts with the resin through an exchange reaction, forming a drug-resin complex. Additionally, the study explored factors influencing the complex formation between the drug and resin, using the drug loading status as an indicator. DSC and ATR studies were carried out to confirm the formation of the drug-resin complex. Subsequently, hot melt granulation was employed to create a matrix tablet incorporating Kollidon® SR and Kollicoat® MAE 100P, thereby enabling sustained release properties. The drug-resin complex embedded in the matrix effectively deters abuse through methods like smoking, snorting, or parenteral injection, unless the drug can be extracted. In order to assess this, solvent extraction studies were conducted using an FDA-recommended solvents, determining the potential for abuse. Further investigations involved dissolution tests in change-over media, confirming the extended-release properties of the formulation. Results from dissolution studies comparing the ground and intact tablets provided positive evidence of the formulation's effectiveness in deterring abuse. Finally, alcohol-induced dose-dumping studies were conducted in compliance with FDA guidelines, concluding that the formulation successfully mitigates dose dumping in the presence of alcohol.

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation-Where Are We Now?

Hot-melt extrusion (HME) is a globally recognized, robust, effective technology that enhances the bioavailability of poorly soluble active pharmaceutical ingredients and offers an efficient continuous manufacturing process. The twin-screw extruder (TSE) offers an extremely resourceful customizable mixer that is used for continuous compounding and granulation by using different combinations of conveying elements, kneading elements (forward and reverse configuration), and distributive mixing elements. TSE is thus efficiently utilized for dry, wet, or melt granulation not only to manufacture dosage forms such as tablets, capsules, or granule-filled sachets, but also for designing novel formulations such as dry powder inhalers, drying units for granules, nanoextrusion, 3D printing, complexation, and amorphous solid dispersions. Over the past decades, combined academic and pharmaceutical industry collaborations have driven novel innovations for HME technology, which has resulted in a substantial increase in published articles and patents. This article summarizes the challenges and models for executing HME scale-up. Additionally, it covers the benefits of continuous manufacturing, process analytical technology (PAT) considerations, and regulatory requirements. In summary, this well-designed review builds upon our earlier publication, probing deeper into the potential of twin-screw extruders (TSE) for various new applications.

3D printing in vaginal drug delivery: a revolution in pharmaceutical manufacturing.

INTRODUCTION: The Food and Drug Administration's approval of the first three-dimensional (3D) printed tablet, Spritam®, led to a burgeoning interest in using 3D printing to fabricate numerous drug delivery systems for different routes of administration. The high degree of manufacturing flexibility achieved through 3D printing facilitates the preparation of dosage forms with many actives with complex and tailored release profiles that can address individual patient needs. AREAS COVERED: This comprehensive review provides an in-depth look into the several 3D printing technologies currently utilized in pharmaceutical research. Additionally, the review delves into vaginal anatomy and physiology, 3D-printed drug delivery systems for vaginal applications, the latest research studies, and the challenges of 3D printing technology and future possibilities. EXPERT OPINION: 3D printing technology can produce drug-delivery devices or implants optimized for vaginal applications, including vaginal rings, intra-vaginal inserts, or biodegradable microdevices loaded with drugs, all custom-tailored to deliver specific medications with controlled release profiles. However, though the potential of 3D printing in vaginal drug delivery is promising, there are still challenges and regulatory hurdles to overcome before these technologies can be widely adopted and approved for clinical use. Extensive research and testing are necessary to ensure safety, effectiveness, and biocompatibility.

Continuous Manufacturing of Solvent-Free Cyclodextrin Inclusion Complexes for Enhanced Drug Solubility via Hot-Melt Extrusion: A Quality by Design Approach.

Conventional cyclodextrin complexation enhances the solubility of poorly soluble drugs but is solvent-intensive and environmentally unfavorable. This study evaluated solvent-free hot-melt extrusion (HME) for forming cyclodextrin inclusion complexes to improve the solubility and dissolution of ibuprofen (IBU). Molecular docking confirmed IBU's hosting in Hydroxypropyl-ß-cyclodextrin (HPß-CD), while phase solubility revealed its complex stoichiometry and stability. In addition, an 11 mm twin-screw co-rotating extruder with PVP VA-64 as an auxiliary substance aided the complex formation and extrusion. Using QbD and the Box-Behnken design, we studied variables (barrel temperature, screw speed, and polymer concentration) and their impact on solubility and dissolution. The high polymer concentration and high screw speeds positively affected the dependent variables. However, higher temperatures had a negative effect. The lowest barrel temperature set near the Tg of the polymer, when combined with high polymer concentrations, resulted in high torques in HME and halted the extrusion process. Therefore, the temperature and polymer concentration should be selected to provide sufficient melt viscosities to aid the complex formation and extrusion process. Studies such as DSC and XRD revealed the amorphous conversion of IBU, while the inclusion complex formation was demonstrated by ATR and NMR studies. The dissolution of ternary inclusion complexes (TIC) produced from HME was found to be ≥85% released within 30 min. This finding implied the high solubility of IBU, according to the US FDA 2018 guidance for highly soluble compounds containing immediate-release solid oral dosage forms. Overall, the studies revealed the effect of various process parameters on the formation of CD inclusion complexes via HME.

Hard Gelatin Capsules Containing Hot Melt Extruded Solid Crystal Suspension of Carbamazepine for improving dissolution: Preparation and In vitro Evaluation.

Aqueous solubility is one of the key parameters for achieving the desired drug concentration in systemic circulation for better therapeutic outcomes. Carbamazepine (CBZ) is practically insoluble in water, is a BCS class II drug, and exhibits dissolution-dependent oral bioavailability. This study explored a novel application of hot-melt extrusion in the manufacture and development of a thermodynamically stable solid crystal suspension (SCS) to improve the solubility and dissolution rate of CBZ. The SCSs were prepared using sugar alcohols, such as mannitol or xylitol, as crystalline carriers. The drug-sugar blend was processed by hot melt extrusion up to 40 % (w/w) drug loading. The extruded SCS was evaluated for drug content, saturation solubility, differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), in vitro release, and stability studies. The physicochemical characterization revealed the highly crystalline existence of pure drug, pure carriers, and extruded SCS. FTIR analysis did not reveal any physical or chemical incompatibilities between the drug and sugar alcohols and showed a homogeneous CBZ distribution within respective crystalline carriers. The SEM micrographs of the solidified SCS revealed the presence of approximately 100 µm crystalline agglomerates. In vitro dissolution and solubility studies showed that the CBZ dissolution rate and solubility were improved significantly from both crystalline carriers for all tested drug loads. The SCSs showed no significant changes in drug content, in vitro release profiles, and thermal characteristics over 3 months of storage at accelerated stability conditions (40±2°C/75±5% RH). As a result, it can be inferred that the SCS strategy can be employed as a contemporary alternative technique to improve the dissolution rate of BCS class II drugs via HME technology.

Drug complexes: Perspective from Academic Research and Pharmaceutical Market.

Despite numerous research efforts, drug delivery through the oral route remains a major challenge to formulation scientists. The oral delivery of drugs poses a significant challenge because more than 40% of new chemical entities are practically insoluble in water. Low aqueous solubility is the main problem encountered during the formulation development of new actives and for generic development. A complexation approach has been widely investigated to address this issue, which subsequently improves the bioavailability of these drugs. This review discusses the various types of complexes such as metal complex (drug-metal ion), organic molecules (drug-caffeine or drug-hydrophilic polymer), inclusion complex (drug-cyclodextrin), and pharmacosomes (drug-phospholipids) that improves the aqueous solubility, dissolution, and permeability of the drug along with the numerous case studies reported in the literature. Besides improving solubility, drug-complexation provides versatile functions like improving stability, reducing the toxicity of drugs, increasing or decreasing the dissolution rate, and enhancing bioavailability and biodistribution. Apart, various methods to predict the stoichiometric ratio of reactants and the stability of the developed complex are discussed.