Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion. II: Rheological Analysis and Extrudability Testing.

Although hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used as a carrier for amorphous solid dispersion of poorly water-soluble drugs, its application has mostly been limited to spray drying, and the solvent-free method of hot melt extrusion has rarely been used. This is on account of the high temperature (≥170°C) required for extrusion where the polymer and even a drug may degrade. In part 1 of this series of papers, we demonstrated that HPMCAS is miscible with surfactants such as, poloxamer 188, poloxamer 407 and d-alpha tocopheryl polyethylene glycol 1000 succinate, which may also serve as plasticizers (Solanki et al., J Pharm Sci. 2019; 108 (4):1453-1465). The present investigation was undertaken to determine plasticization effects of the surfactants and a model drug, itraconazole, in reducing melt extrusion temperatures of HPMCAS. The determination of complex viscosity as functions of temperature and also as functions of angular frequency at certain fixed temperatures showed that the surfactants and the drug greatly reduce viscosity of HPMCAS by their plasticization effects. Surfactants and drug also had synergistic effects in reducing viscosity. The torque analysis during melt extrusion demonstrated that these additives greatly enhanced extrudability of HPMCAS. Surfactant-drug-polymer mixtures were successfully extruded as stable amorphous solid dispersions at 130°C, which is much lower than the minimum extrusion temperature of 170°C for neat HPMCAS.

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model.

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon® C-50; m.p. ∼50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel™ EXF was first evaluated by film casting, and Kollidon® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon® C-50, and the remaining Kollidon® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon® C-50, up to 20% each, as well as Kollidon® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.

Effects of Surfactants on Itraconazole-HPMCAS Solid Dispersion Prepared by Hot-Melt Extrusion I: Miscibility and Drug Release.

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely investigated as a carrier for amorphous solid dispersion (ASD) of poorly water-soluble drugs. However, its use has mostly been limited to ASDs prepared by spray drying using organic solvents, and the solvent-free method, hot-melt extrusion (HME), has only limited use because it requires high processing temperature where the polymer and drug may degrade. In this investigation, surfactants were used as plasticizers to reduce the processing temperature. Their effects on drug release were also determined. To determine suitability of using surfactants, the miscibility of HPMCAS with 3 surfactants (poloxamer 188, poloxamer 407, and d-alpha tocopheryl polyethylene glycol 1000 succinate) and a model drug, itraconazole (ITZ), was studied by film casting. HPMCAS was miscible with ITZ (>30%) and each surfactant (>20%), and in ternary HPMCAS-ITZ-surfactant (60:20:20) system. ASDs prepared by HME of HPMCAS-ITZ-surfactant mixtures (70:20:10 and 65:20:15) at 160°C were physically stable after exposure to 40°C and 75% relative humidity for 1 month. The presence of 15% w/w surfactant provided up to 50% drug release at pH 1 as compared to only 8% from ASDs with HPMCAS alone. On changing the pH of the dissolution medium from 1 to 6.8 in a step-dissolution process, complete drug release (90%-100%) and extremely high apparent supersaturation (∼75,000 times) of ITZ were observed when the solutions were filtered through 0.45 µm filters. The apparently supersaturated solutions consisted of colloidal particles of ∼300 nm size. The present study demonstrates that stable ASDs with improved processability and drug release may be prepared by HME.

Effect of the Interaction Between an Ionic Surfactant and Polymer on the Dissolution of a Poorly Soluble Drug.

Surfactants are commonly incorporated in conventional and enabled formulations to enhance the rate and extent of dissolution of drugs exhibiting poor aqueous solubility. Generally the interactions between the drug and excipients are systematically evaluated, however, limited attention is paid towards understanding the effect of interaction between functional excipients and its impact on the performance of the product. In the current study, the effect of potential interaction between a nonionic polymer binder, povidone, and anionic surfactant docusate sodium on the rate and extent of dissolution of a drug exhibiting poor aqueous solubility was evaluated by varying the proportions of the binder and the surfactant in the formulation. Potential complexation or aggregation between the excipients was investigated by fluorescence spectroscopy and zeta potential measurements of the aqueous solutions of docusate sodium, povidone, and sodium lauryl sulfate (SLS). The rate and extent of drug release was found to decrease with an increase in the proportion of docusate sodium and povidone in the formulations. Difference in magnitude of surface charge (zeta potential) of docusate sodium in presence of povidone indicated potential surfactant-polymer aggregation during dissolution which was corroborated by CAC/CMC values derived from fluorescence spectroscopic measurements. The decrease in the rate of drug release was attributed to an increase in the viscosity of the microenvironment of dissolving particles due to the interaction of docusate sodium and povidone in the aqueous media during dissolution. These findings highlight the importance of systematic evaluation of the interaction of ionic surfactants with the polymeric components within the formulation to ensure the appropriate selection of the type of surfactant as well as its proportion in the formulation.

Development of solid SEDDS, VII: Effect of pore size of silica on drug release from adsorbed self-emulsifying lipid-based formulations.

PURPOSE: Lipid-based self-emulsifying drug delivery systems (SEDDS) are usually liquids, and they can be converted into solid dosage forms by adsorbing onto silicates. However, most commercially available silicates are mesoporous with small pore sizes of 1 to 50nm that lead to incomplete emulsification of SEDDS inside the pores and thus incomplete drug release. The objective of this study was to investigate the impact of silica pore size on the extent of drug release from SEDDS solidified by adsorbing onto macroporous silicas with different pore sizes. METHODS: Silicas with average pore sizes of approx. 150nm, 500nm and 5µm were synthesized using the colloidal crystal templating method. A model poorly water-soluble drug, probucol, was dissolved in liquid SEDDS containing different lipid to surfactant ratios, and the formulations were then adsorbed onto equal weights of silicas (1:1 w/w ratio). Drug release from freshly prepared formulations and after storing at 40°C/60% RH for up to 6months was studied using a modified USP type 2 method with mini paddles and 50mL of 0.01M HCl (pH~2) at 37°C. Drug release was also studied similarly from silicas that were precoated with PVP K-30 at 5, 10, 20 and 30% w/w levels before adsorption of SEDDS. RESULTS: Freshly prepared formulations containing relatively higher lipid:surfactant ratio of 7:3% w/w exhibited 17, 40 and 60% drug release from uncoated (neat) silicas with pore sizes of 150nm, 500nm and 5µm, respectively, while the more hydrophilic formulations containing 3:7 w/w lipid:surfactant ratio had, respectively, 50, 65 and 85% drug release. No decrease in drug release was observed when the formulations were exposed to 40°C/60% RH for up to 6months. When the silicas were precoated with 20% PVP, the drug release was almost complete (>80%), which remained unchanged even after 6months of storage irrespective of the composition of adsorbed liquid SEDDS. CONCLUSIONS: Both pore size and composition of SEDDS had major impacts on drug release from silicas. Increased drug release was observed with the increase in pore size of silicas and hydrophilicity of formulations. Since the silicas synthesized were macroporous with no mesopores present, there was no decrease in drug release upon storage. Complete drug release was observed when silicas were precoated with PVP as it increased the penetration of water into the pores.

Development of solid SEDDS, VI: Effect of precoating of Neusilin® US2 with PVP on drug release from adsorbed self-emulsifying lipid-based formulations.

Adsorption of lipid-based formulations, which are usually liquid, onto silicas has been extensively investigated in the past decade to convert them into solid dosage forms. There are conflicting reports on the ability of commercially available porous silicas, like Neusilin® US2, to release lipid formulations completely, especially after long-term storage. In this study, the release of a model drug, probucol, from different formulations of medium chain lipids and a surfactant, Kolliphor EL (Cremophor EL) or polysorbate 80, were studied after adsorbing them onto Neusilin® US2. Complete drug release (>80%) was obtained from all formulations on Day 1; however, the extent of drug release decreased progressively with time. The decrease was dependent on the relative hydrophilicity of the formulations. The maximum decrease (<10% drug released on day 60) was seen from formulations containing the highest amount of lipid (70% in the SEDDS preconcentrate) and lowest decrease was seen in formulations containing the drug dissolved in the neat surfactant only (ca. 65% drug released on day 60). Precoating Neusilin® US2 with polyvinylpyrrolidone (PVP), by treating the silicate with an alcoholic solution of PVP and then drying, eliminated or minimized the decrease in drug release upon storage, possibly by blocking the mesoporous region of the silicate and improving hydration and allowing emulsification of the formulations within the larger pores. Formulations containing PVP K-90 precoated on Neusilin® US2 exhibited complete drug release (>80%) even after 6months of storage.

Investigation of Polymer-Surfactant and Polymer-Drug-Surfactant Miscibility for Solid Dispersion.

In a solid dispersion (SD), the drug is generally dispersed either molecularly or in the amorphous state in polymeric carriers, and the addition of a surfactant is often important to ensure drug release from such a system. The objective of this investigation was to screen systematically polymer-surfactant and polymer-drug-surfactant miscibility by using the film casting method. Miscibility of the crystalline solid surfactant, poloxamer 188, with two commonly used amorphous polymeric carriers, Soluplus® and HPMCAS, was first studied. Then, polymer-drug-surfactant miscibility was determined using itraconazole as the model drug, and ternary phase diagrams were constructed. The casted films were examined by DSC, PXRD and polarized light microscopy for any crystallization or phase separation of surfactant, drug or both in freshly prepared films and after exposure to 40°C/75% RH for 7, 14, and 30 days. The miscibility of poloxamer 188 with Soluplus® was <10% w/w, while its miscibility with HPMCAS was at least 30% w/w. Although itraconazole by itself was miscible with Soluplus® up to 40% w/w, the presence of poloxamer drastically reduced its miscibility to <10%. In contrast, poloxamer 188 had minimal impact on HPMCAS-itraconazole miscibility. For example, the phase diagram showed amorphous miscibility of HPMCAS, itraconazole, and poloxamer 188 at 54, 23, and 23% w/w, respectively, even after exposure to 40°C/75% RH for 1 month. Thus, a relatively simple and practical method of screening miscibility of different components and ultimately physical stability of SD is provided. The results also identify the HPMCAS-poloxamer 188 mixture as an optimal surface-active carrier system for SD.

Development of Solid SEDDS, V: Compaction and Drug Release Properties of Tablets Prepared by Adsorbing Lipid-Based Formulations onto Neusilin® US2.

PURPOSE: To develop tablet formulations by adsorbing liquid self-emulsifying drug delivery systems (SEDDS) onto Neusilin®US2, a porous silicate. METHODS: Nine SEDDS were prepared by combining a medium chain monoglyceride, Capmul MCM EP, a medium chain triglyceride, Captex 355 EP/NF, or their mixtures with a surfactant Cremophor EL, and a model drug, probucol, was then dissolved. The solutions were directly adsorbed onto Neusilin®US2 at 1:1 w/w ratio. Content uniformity, bulk and tap density, compressibility index, Hausner ratio and angle of repose of the powders formed were determined. The powders were then compressed into tablets. The dispersion of SEDDS from tablets was studied in 250 mL of 0.01NHCl (USP dissolution apparatus; 50 RPM; 37°C) and compared with that of liquid SEDDS. RESULTS: After adsorption of liquid SEDDS onto Neusilin®US2, all powders demonstrated acceptable flow properties and content uniformity for development into tablet. Tablets with good tensile strength (>1 MPa) at the compression pressure of 45 to 135 MPa were obtained. Complete drug release from tablets was observed if the SEDDS did not form gels in contact with water; the gel formation clogged pores of the silicate and trapped the liquid inside pores. CONCLUSION: Liquid SEDDS were successfully developed into tablets by adsorbing them onto Neusilin®US2. Complete drug release from tablets could be obtained.

Development of Solid SEDDS, IV: Effect of Adsorbed Lipid and Surfactant on Tableting Properties and Surface Structures of Different Silicates.

PURPOSE: To compare six commonly available silicates for their suitability to develop tablets by adsorbing components of liquid lipid-based drug delivery systems. METHODS: The tabletability of Aerosil® 200, Sipernat® 22, Sylysia® 350, Zeopharm® 600, Neusilin® US2 and Neusilin® UFL2 were studied by compressing each silicate into tablets in the presence of 20% microcrystalline cellulose and measuring the tensile strength of tablets produced. Three components of lipid based formulations, namely, Capmul® MCM EP (glycerol monocaprylocaprate), Captex® 355 EP/NF (caprylic/capric triglycerides) and Cremophor® EL (PEG-35 castor oil), were adsorbed individually onto the silicates at 1:1 w/w, and the mixtures were then compressed into tablets. The SEM photomicrographs of neat silicates and their 1:1 w/w mixtures (also 1:2 and 1:3 for Neusilin® US2 and Neusilin® UFL2) with one of the liquids (Cremophor® EL) were recorded. RESULTS: Neat Aerosil® 200, Sipernat® 22 and Sylysia® 350 were non-tabletable to the minimum acceptable tensile strength of 1 MPa, and they were also non-tabletable in presence of liquid. While Zeopharm® 600, Neusilin® US2 and Neusilin® UFL2 were tabletable without the addition of liquids, only Neusilin® US2 retained acceptable tabletability with 1:1 liquid. The SEM images of silicate-liquid mixtures indicated that, except for Neusilin® US2, much of the adsorbed liquid distributed primarily at the surface of particles rather than inside pores, which hindered their compaction into tablets. CONCLUSION: Among the six silicates studied, Neusilin® US2 was the only silicate able to produce tablets with acceptable tensile strength in presence of a lipid component at 1:1 w/w ratio due to the fact that the liquid was mostly adsorbed into the pores of the silicate rather than at the surface.