Mechanochemical synthesis of hydrochlorothiazide-nicotinamide cocrystal: from batch-based ball-milling to scale-up ready hot melt extrusion.

The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal

Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.

Controlled-release drug delivery systems (CRDDS) are more beneficial than conventional immediate release (IRDDS) for reduced intake, prolonged duration of action, lesser adverse effects, higher bioavailability, etc. The preparation of CRDDS is more complex than IRDDS. The hot melt extrusion (HME) technique is used for developing amorphous solid dispersion of poorly water soluble drugs to improve their dissolution rate and oral bioavailability. HME can be employed to develop CRDDS. Sustained release delivery systems (SRDDS), usually given orally, can also be developed using HME. This technique has the advantages of using no organic solvent, converting crystalline drugs to amorphous, improving bioavailability, etc. However, the heat sensitivity of drugs, miscibility between drug-polymer, and the availability of a few polymers are some of the challenges HME faces in developing CRDDS and SRDDS. The selection of a suitable polymer and the optimization of the process with the help of the QbD principle are two important aspects of the successful application of HME. In this review, strategies to prepare SRDDS and CRDDS using HME are discussed with its applications in research.

Hot melt extrusion (HME) is a powerful technology to enhance the solubility and bioavailability of poorly water-soluble drugs by producing amorphous solid dispersions. Although the number of articles and patents about HME increased dramatically in the past twenty years, there are very few commercial products by far. The three main obstacles limiting the commercial application of HME are summarized as thermal degradation of heat-sensitive drugs at high process temperature, recrystallization of amorphous drugs during storage and dissolving process, and difficulty to obtain products with reproducible physicochemical properties. Many efforts have been taken in recent years to understand the basic mechanism underlying these obstacles and then to overcome them. This article reviewed and summarized the limitations, recent advances, and future prospects of HME.

This study focuses on the application of hot melt extrusion (HME) to produce solid dispersions containing griseofulvin (GF) and investigates the in-vitro dissolution performance of HME powders and resulting tablet compositions containing HME-processed dispersions. Binary, ternary and quaternary dispersions containing GF, enteric polymer (Eudragit L100-55 or AQOAT-LF) and/or vinyl pyrrolidone-based polymer (Plasdone K-12 povidone or S-630 copovidone) were processed by HME. Two plasticizers, triethyl citrate (TEC) and acetyl tributyl citrate (ATBC), were incorporated to aid in melt processing and to modify release of GF in neutral media following a pH-change in dissolution. Products were characterized for GF recovery, degrees of compositional amorphous character, intermolecular interactions and non-sink dissolution performance. Binary dispersions exhibited lower maximum observed concentration values and magnitudes of supersaturated GF in neutral media dissolution in comparison with the ternary dispersions. The quaternary HME products, 1 : 2 : 1 : 0.6 GF : L100-55 : S-630 : ATBC and GF : AQOAT-LF : K-12 : ATBC, were determined as the most optimal concentration-enhancing compositions due to increased hydrogen bonding of enteric functional groups with carbonyl/acetate groups of vinyl pyrrolidone-based polymers, reduced compositional crystallinity and presence of incorporated hydrophobic plasticizer. HME products containing combinations of concentration-enhancing polymers can supersaturate and sustain GF dissolution to greater magnitudes in neutral media following the pH-transition and be compressed into immediate-release tablets exhibiting similar dissolution profiles.

Hot Melt Extrusion (HME) is an innovative approach that is currently receiving significant interest in the pharmaceutical sector for the manufacturing of various dosage forms. This technique entails the melting and extruding of a mixture of pharmaceutical drugs and polymeric carriers, resulting in solid dispersions or more sophisticated formulations. This review examines the historical development of HME and its foundational applications in pharmaceutical manufacturing. It also provides an overview of the type of extruders used for hot melt extrusion and analyzes the essential extrusion parameters that affect the qualities of the product. Furthermore, it analyzes the variety of materials appropriate for HME, including both active pharmaceutical ingredients and polymeric carriers. HME is not only a validated manufacturing method but also aligns with the objectives of the US Food and Drug Administration's (FDA) process analytical technology (PAT) framework for the design, analysis, and control of production through quality control metrics throughout the active extrusion process. From a comprehensive viewpoint, hot-melt extrusion technology encompasses its components, processing technologies, materials and innovative formulation designs and advancements in many applications for oral drug delivery system. Keywords: Screw extruders, manufacturing, solubility, bioavailability, extrusion, solubility enhancement

Hot melt extrusion (HME), a technology which mixing the advantages of solid dispersion technology and mechanical preparation, is accepted in varied applications in pharmaceutical formulations. When combined with other techniques, such as nanotechnique, three-dimensional printing, and co-extrusion, HME becomes much more multifunctional in the application of drug delivery. While in most cases, polymers employed in HME are responsible for the final property of products. The process of HME together with the selection of materials employed in HME were described briefly. In addition, the applications of HME in drug delivery and its currently status in the pharmaceutical field were also included. Some commercial products produced by HME have met the approval of FDA, indicating the commercial viability of this technique. Although showing great potential in pharmaceutical manufacturing, HME is still challenged by high temperature, shear force, and high input energy. Development of equipment, modifying the parameters, and optimization of polymeric formulations are needed for a safe, effective, and multifunctional hot melt extrusion drug delivery system. Also, wider range of combinations between HME and other techniques may provide guideline for developing multiple applications in drug delivery.

This research examined the application of hot melt extrusion (HME) in the preparation of matrix formulations containing hydroxypropyl cellulose (HPC) as a base polymer in combination with methyl cellulose (MC) and hydroxypropyl methylcellulose (HPMC). The limit to which formulations could control drug release under varying paddle speeds, high alcohol environments and high and low drug loads was investigated on a Caleva 10 ST dissolution tester. Rheological studies and hot plate imaging highlighted the impact of thermoresponsive polymers on drug release. The rate and percentage release of drug were analysed using a one-way ANOVA and Tukey's HSD test. No significant differences in the amount of drug released were calculated as a result of paddle speed variation or in the presence of 40% v/v ETOH. The phase separation effects of temperature-sensitive polymers HPC and MC and the characteristic gel shrinkage and fluid expulsion were shown to be contributing factors. The use of the partition activity, α, identified the extent to which formulations were affected by phase separation. Hot melt extrusion was successfully used to manufacture cellulose-based formulations. Thermoresponsive polymers HPC and MC significantly impacted drug release properties.

Pharmaceutical cocrystals are still gaining the interest of the researchers due to their potential to alter physicochemical, mechanical, and pharmacokinetic properties of active pharmaceutical ingredients without negotiating therapeutic action. The diverse new applications of cocrystals, like taste masking, reduced toxicity, patenting opportunities, commercial potential, etc. act as driving force to the rising interest of the pharmaceutical industries. Initially, cocrystals from the view of regulatory authorities, design strategies, cocrystal preparation in brief with special emphasis on scalable and solvent-free hot melt extrusion method, and practical guide to characterization have been provided. The special focus has been given to the biopharmaceutical attributes of the cocrystal. Finally, challenges before and after cocrystal preparation are presented in this review along with some commercial examples of the cocrystals.

Polymeric formulations for drug release prepared by hot melt extrusion: application and characterization

The pharmaceutical co-crystal has attracted increasing interest due to the improvement of physicochemical properties of active pharmaceutical ingredients. The characterization of pharmaceutical co-crystal is an integral part of the pharmaceutical field. In this paper, the low-frequency vibrational properties for carbamazepine co-crystals with nicotinamide and saccharin (CBZ-NIC and CBZ-SAC) have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experiment results show that, compared with the individual constituents, CBZ-NIC and CBZ-SAC co-crystals not only have different characteristic absorption peaks in the 0.3-2.5 THz region, but also have significant low-wavenumber Raman characteristic peaks in 0–100 cm−1. Density functional theory was performed to simulate the terahertz and low-wavenumber Raman spectra of the two co-crystals, where the calculation agreed well with the measured vibrational peak positions. The vibrational modes of CBZ-NIC and CBZ-SAC co-crystals were assigned through comparing theoretical results with the experimental spectra. Meanwhile, the low-frequency infrared and/or Raman active of characteristic peaks for such co-crystals were discussed. The results indicate the combination of THz spectroscopy and low-wavenumber Raman spectroscopy can provide more comprehensive low-frequency vibrational information for pharmaceutical co-crystals, such as collective vibration and skeleton vibration, which could play an important role in pharmaceutical science.

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

Objective Hot-melt extrusion (HME) has emerged as a solvent-free, scalable, efficient, and continuous process to overcome the challenges of poor solubility in new drug entities. Using HME technique, crystalline drugs are converted to amorphous solid dispersions (ASDs), which significantly enhances their dissolution rates and oral bioavailability. This review is aimed to provide a comprehensive review of HME as a transformative strategy in pharmaceutical manufacturing. Significance of review This review critically analyzes the mechanistic insights of solubility enhancement using HME, its advantages over traditional methods, key formulation components, and the influence of processing parameters on drug stability and performance. Moreover, translational case studies emphasizing the applications of HME in solubility enhancement, and the growing role of artificial intelligence (AI) and molecular modeling are discussed in detail. It also covers the patent landscape relevant to HME and compares HME with other methods of ASD preparation. Key findings The literature indicated that recent technological advancements in HME including nanocrystal generation, co-crystallization, hybrid methods, and three-dimensional printing integration garners its immense potential and highlighting its wide scope of applications. Recent integration of AI and machine learning (ML) with HME has emerged as a forward-looking strategy that can be employed successfully in the optimization of formulation design and manufacturing. Conclusions The continuous processing capabilities, adaptability to various dosage forms, and compatibility with modern drug development strategies have highlighted the importance and versatile applications of HME. Moreover, growing regulatory acceptance and continuous innovations have placed HME at the forefront of pharmaceutical development for poorly soluble compounds.

Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations.

Introduction. The extremely unfavorable physical, chemical and functional properties of diosmin, a component of a number of popular phleboprotective drugs, cause an increased therapeutic dosage of the active pharmaceutical ingredient (API) in the dosage form and complicate the manufacturing process. In order to improve the characteristics of API, a technology of solid dispersion systems (SDS) creation by hot melt extrusion (HME) has been proposed. Particular importance in the context of current approach is attached to the selection of an effective polymer matrix.Aim. The selection and justification of using a polymer carrier from the polyvinylpyrrolidone group for creating diosmin solid dispersions by hot melt extrusion.Materials and methods. Object of study: diosmin (powder micronized substance, Chengdu Runde Pharmaceutical Co., Ltd., China). As candidates for the development of solid dispersions with a model ratio of API to carrier of 1 : 99, two related hydrophilic polymers were selected: a copolymer of polyvinylpyrrolidone with vinyl acetate in a ratio of 60 : 40 (PVPVA) – VIVAPHARM® PVP/VA 64 (JRS PHARMA GmbH & Co. KG, Germany), and polyvinylpyrrolidone brand Kollidon® K17 PF (BASF, USA). The thermal properties of the API and polymer carrier were characterized using synchronous thermal analysis. Diosmin SDS were obtained using a HAAKE™ MiniCTW twin-screw extruder (Thermo Fisher Scientific, Germany). The quantitative content of diosmin in the solid dispersions was determined by HPLC. To assess the effect of the extrusion process on the sample characteristics, the functional properties of API and milled SDS were compared. In particular, the thermal and structural characteristics were studied using differential scanning calorimetry and FTIR spectroscopy, respectively.Results and discussion. Kollidon® K17 is not effective in binary diosmin solid dispersions due to the increased viscosity of the melt, the risk of forming a heterogeneous system, and the potential degradation of the samples' functional properties relative to the pure micronized API. Taking into account the specifics of the extrusion process, as well as the results of the thermal, structural, and functional characteristics analysis of SDS, it was concluded that copolymer of polyvinylpyrrolidone with vinyl acetate is the most effective. This polymer matrix enables more uniform dispersion and fusion with diosmin, along with a tendency towards possible amorphization of the API, and thus – the possibility of solubility properties improvement.Conclusion. The utilization of a copolymer of polyvinylpyrrolidone with vinyl acetate improves the unfavorable characteristics of micronized diosmin, which will eventually eliminate deviations during the manufacturing process of solid dosage forms by reducing the risks of dust formation and mechanical losses, as well as ensuring uniform dosing.