Formulation and Assessment of Gliclazide Solid Dispersions

Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs.

ABSTRACTIntroduction: As a consequence of the target and drug candidate identification process, drugs with higher hydrophobicity and/or lipophilicity are being selected for further development, leading to solubility and dissolution rate limited oral bioavailability, and hence potential failure of the intended therapeutic goal. Solid dispersions were introduced as a formulation strategy in the early 1960s to tackle this issue and are still an area of intensive research activity.Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.

BackgroundSoluplus® (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)–based solid dispersion (SD) formulations were developed by hot-melt extrusion (HME) to improve oral bioavailability of valsartan (VST).MethodsHME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST.ResultsHME with a high shear rate produced by the twin-screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group.ConclusionSP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs.

Pitavastatin (PTV) is a potent lipid lowering drug that acts on hepatocytes by blocking the 3-hydroxy-3- methylglutaryl-CoA reductase enzyme. As a Biopharmaceutical Classification System (BCS) Class II drug, PTV possesses very low water solubility; hence, poor bioavailability leads to poor drug delivery to the target organ. The study aims to develop various PTV solid dispersion (SD) formulations and to investigate the release profile of PTV SD systems. Different PTV physical mixing and SD formulations were prepared using polyvinylpyrrolidone (Kollidon®90F) and Kollicoat®IR hydrophilic polymers by fusion and solvent evaporation approaches. The efficacy of the formulations was evaluated by in vitro PTV release studies. Subsequently, the characterization of SD formulations was performed using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The in vitro release studies confirmed that all the developed formulations showed a comparatively better release percentage (75.31–98.45%) than the pure PTV (61.76%) after 60 min. Additionally, the outcomes showed that raising the concentration of both polymers improved PTV's ability to dissolve. In comparison to physical mixing formulations, SD formulations made using fusion and solvent evaporation processes performed better during dissolution. The TGA, DSC, and FTIR studies confirmed that the tested SD formulations (1:2, 1:3 ratios) were stable at high temperatures with a reduction in crystallinity and no notable interaction between the drug and polymers. The SEM analysis showed that the PTV was evenly spread out in the carriers and that the crystal-like structure of the PTV had changed into an amorphous form. Bangladesh Pharmaceutical Journal 27(1): 37-50, 2024 (January)

This study aimed to isolate a lignan-enriched fraction from Schisandra chinensis and improve the dissolution of biologically active lignans via solid dispersion (SD) formulation. Lignan-enriched fraction was obtained from a hexane-soluble extraction, being poorly soluble in water. To improve the dissolution of major lignans from these extracts, SD formulation of an isolated extract was prepared with different hydrophilic polymers. Among the tested carriers, poloxamer 407 was most effective in enhancing the release of active lignans from extract. Compared to the pure extract, poloxamer 407-based SD significantly increased the dissolution of nine active lignans (schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, schisandrin B, gomisin N, schisandrin C) by 1.6- to 300-fold in water. SD also lead to the solidification of sticky extract, providing better flowability and ease of handling. Collectively, poloxamer 407-based SD formulation appeared to be effective in enhancing the dissolution of the active lignans from S. Chinensis.

Design of Coenzyme Q10 solid dispersion for improved solubilization and stability.

The aim of this study was to investigate the effects of solid dispersions (SD) and self-emulsifying (SE) formulations on the solubility and absorption properties of active components in total flavones of Hippophae rhamnoides L. (TFH). The solubility, dissolution rate, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in TFH SD/SE formulations and TFH were compared. The results showed that the solubility and dissolution rate of isorhamnetin, quercetin and kaempferol in SD/SE formulations were significantly enhanced compared to those in TFH, however, their intestinal permeability was comparable. The bioavailability of isorhamnetin, quercetin and kaempferol in rats remarkably increased after oral administration of TFH SD formulations compared to TFH, but there was no significant increase after oral administration of TFH SE formulations. The results of this study indicated the SD formulations on the improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH were much better than those of SE formulations. The improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH by SD formulations was probably ascribed to the enhancement of the solubility and dissolution of the three components, but was not relevant to the intestinal permeability. Therefore, as for herb extracts containing multiple components, especially for their major components with poor water solubility, solid dispersion formulations might have the better potential to enhance their bioavailability.

Amorphous solid dispersion (ASD) formulations are routinely used to enable the delivery of poorly soluble compounds. This type of formulations can enhance bioavailability due to higher kinetic solubility of the drug substance and increased dissolution rate of the formulation, by the virtue of the fact that the drug molecule exists in the formulation in a high energy amorphous state. In this article we report the application of physiologically based absorption models to mechanistically understand the clinical pharmacokinetics of solid dispersion formulations. Three case studies are shown here to cover a wide range of ASD bioperformance in human and modeling to retrospectively understand their in vivo behavior. Case study 1 is an example of fairly linear PK observed with dose escalation and the use of amorphous solubility to predict bioperformance. Case study 2 demonstrates the development of a model that was able to accurately predict the decrease in fraction absorbed (%Fa) with dose escalation thus demonstrating that such model can be used to predict the clinical bioperformance in the scenario where saturation of absorption is observed. Finally, case study 3 shows the development of an absorption model with the intent to describe the observed incomplete and low absorption in clinic with dose escalation. These case studies highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of ASD performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Formulation and in vitro absorption analysis of Rhizoma paridis steroidal saponins

Comparison of paclitaxel solid dispersion and polymeric micelles for improved oral bioavailability and in vitro anti-cancer effects

Enhanced systemic exposure of saquinavir via the concomitant use of curcumin-loaded solid dispersion in rats

The overall aim of the thesis was to introduce new analytical techniques to characterize solid dispersion formulations. Solid dispersion formulations are employed to enhance the dissolution behavior and apparent solubility of poorly soluble compounds. This formulation strategy uses typically an amorphous physical form of a poorly soluble drug and combines it with a carrier for stabilization. The amorphous form presents higher free energy compared to a crystalline drug form thereby yielding a higher dissolution rate and possibly more complete oral absorption as well as bioavailability. The selection of appropriate excipients is crucial to guarantee the formulation performance and stability during the shelf life of the final product. To investigate drug formulation characteristics and predict their performance, different analytical techniques are needed. Along with the classical characterization techniques, novel approaches such as fluorescence spectroscopy and diffusing wave spectroscopy are introduced in the present thesis. The chapters 1 and 2 of this thesis cover fundamental aspects of poorly soluble drugs: an overview is given on amorphous solid dispersion (ASD) manufacturing technologies and characteristics of polymers and surfactants used in ASD. Moreover, analytical tools to characterize solid dispersions are presented. Among them, special emphasis is given to novel approaches such as Diffusing Wave Spectroscopy (DWS) and Fluorescence Spectroscopy. As for the selection of excipients, drug polymer miscibility is a crucial requisite for the performance of an ASD formulation. One of the methods to predict drug-polymer miscibility is to employ solubility parameter approach; its application in solid dispersion formulations is outlined in the Chapter 3. The first study introduces a novel fluorescence quenching approach together with size exclusion chromatography to study drug-polymer interactions that emerge from ASDs drug release in an aqueous medium. Celecoxib was combined with different pharmaceutical polymers and the resulted solid dispersion was evaluated by the (modified) Stern-Volmer model. Drug accessibility by the quencher and its affinity to the drug were compared in physical mixtures as well as within the ASDs using different polymer types. It was possible to gain knowledge about specific drug-polymer interactions and the amount of drug embedded in the evolving drug-polymer aggregates upon formulation dispersion and drug dissolution. More research in the future will show how such in vitro findings translate into performance of an ASD in vivo. The second study of this thesis has also a biopharmaceutical focus and investigates formulation differences from a microrheological perspective by considering further an in vitro absorption sink using a biphasic dissolution equipment. Indeed, biphasic dissolution testing can simulate an intestinal absorption from dispersed formulation by using an organic layer. This study employed ketoconazole, a poorly soluble drug, together with different grades of HPMCAS and formulations were produced by hot melt extrusion (HME). Diffusing wave spectroscopy highlighted microrheological differences among the different polymer grades and plasticizers in the aqueous phase. These differences were found to influence drug release and finally the uptake in the organic layer that was intended to mirror the absorption process. There is surely more research needed before final conclusions can be drawn but the obtained findings point already to an important contribution of microrheological differences that evolved upon formulation dispersion. The third study also emphasized microrheology but with a focus on non-dispersed solid dispersions. It was aimed to investigate microstructuring during phase transitions in drug-polymer solid dispersions. This formulation microstructuring is critical for the physicochemical properties such as stability of the final dosage form. In this study, eutectic mixtures of polyethylene glycol (PEG) were investigated using two drugs: fenofibrate and flurbiprofen. Unlike fenofibrate, the drug flurbiprofen was strongly interacting with the polymer and this was also confirmed by the rheological characterization. Therefore, broadband DWS provided valuable mechanistic information on the drug-polymer interactions and macromolecular structuring during the cooling of the eutectic melts.

Establishment of new preparation method for solid dispersion formulation of tacrolimus

Characterization of the copolymer poly(ethyleneglycol-g-vinylalcohol) as a potential carrier in the formulation of solid dispersions

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin