Continuous Synthesis of Cinnarizine Salt with Malic Acid by Applying Green Chemistry Using Water-Assisted Twin Screw Extrusion.

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pHmax of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13C and 15N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.

Clofazimine pKa Determination by Potentiometry and Spectrophotometry: Reverse Cosolvent Dependence as an Indicator of the Presence of Dimers in Aqueous Solutions.

The weakly basic antibiotic and anti-inflammatory drug, clofazimine (CFZ), was first described in 1957. It has been used therapeutically, most notably in the treatment of leprosy. However, the compound is extremely insoluble in aqueous media, and, indeed, there is poor consensus about what its intrinsic solubility is since the reported values range from 0.04 to 11 ng/mL. To understand the speciation and solubilization of CFZ as a function of pH, it is of paramount importance to know the true aqueous pKa. However, there is also poor consensus about the value of the pKa (reported measured values range from 6.08 to 9.11). In the present study, we report the determination of the CFZ ionization constant using two independent techniques. A state-of-the-art potentiometric analysis was performed, drawing on titration data in methanol-water solutions (46-75 wt % MeOH) of CFZ, using the bias-reducing consensus of two different procedures of extrapolating the apparent psKa values to zero cosolvent to approximate the true aqueous pKa as 9.43 ± 0.12 (25 °C, I = 0.15 M reference ionic strength). In parallel, spectrophotometric UV/vis titration data were acquired (250-600 nm at different pH) in 10 mM HEPES buffer solutions containing up to 54 wt % MeOH. The alternating least squares (ALS) method was used in the analysis of the absorbance-pH spectra. Uncharacteristically, the cosolvent UV/vis data in our study showed reverse cosolvent dependence (apparent pKa values increased with increasing cosolvent) which could be explained by a dimerization of the free base. The analysis of UV/vis data obtained from 54 wt % MeOH-water solution containing 20 µM CFZ yielded the apparent pKa 9.51 ± 0.17 (I ≈ 0.005 M). To assess whether self-assembly of CFZ was energetically feasible, density functional theory (DFT) calculations were used to study the putative CFZ dimers in aqueous and methanol media. The DFT-optimized geometries and infrared spectra of CFZ dimers using water and methanol as solvents were calculated and analyzed. Based on the lack of negative frequencies in calculated infrared spectra, it was confirmed that optimized geometries correspond to the true energetic minima. Visual analysis of optimized structures indicates the presence of stacking interactions between two CFZ molecules. The protonation site (the imine nitrogen atom) was determined by 1H NMR spectroscopy.

In Vitro Assessment of Cisplatin/Hyaluronan Complex for Loco-Regional Chemotherapy.

Loco-regional chemotherapy is a strategy used to achieve more precise anticancer drug effect directly on tumor mass, while decreasing whole body exposure, which can lead to undesirable side effects. Thus, the loco-regional chemotherapy is conceptually similar to the targeted drug delivery systems for delivering chemotherapeutics to cancer cells in a certain location of the body. Recently, it has been demonstrated that a novel polymeric film containing the complex between cisplatin (cisPt) and hyaluronan (sodium salt of hyaluronic acid; NaHA) enhanced in vivo efficacy and safety of cisplatin (cisPt) by loco-regional delivery in pleural mesothelioma. Biologically, hyaluronic acid (HA) binds with the CD44 receptor, which is a transmembrane glycoprotein overexpressed by other cancer cells. Thus, administering both cisPt and hyaluronan together as a complex loco-regionally to the tumor site could target cancer cells locally and enhance treatment safety. A slight excess of hyaluronan was required to have more than 85% cisPt complexation. In cell monolayers (2D model) the cisPt/NaHA complex in solution demonstrated dose- and time-dependent cytotoxic effect by decreasing the viability of pancreatic, melanoma, and lung cell lines (they all express CD44). At the same concentration in solution, the complex was as effective as cisPt alone. However, when applied as film to melanoma spheroids (3D model), the complex was superior because it prevented the tumor spheroid growth and, more importantly, the formation of new cell colonies. Hence, cisPt/NaHA complex could work in preventing metastases loco-regionally and potentially avoiding systemic relapses.

Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule "Soft" Constraints.

The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published "white paper" (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pH-RSF) method, introduced in our earlier work (Markovic et al., 2019), was applied. An improved and more detailed experimental design of the Nor solubility measurement allowed us to exploit the full capacity of the pH-RSF method. Complex equilibria in the aqueous phase (cationic and anionic complex formation between Nor and the phosphate) and solid-phase transformations (Nor free base, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts) were characterized by a detailed analysis of the solubility measurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustrate the influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth, on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in the formulation of drug products.

Development of self-microemulsifying lipid-based formulations of trans-resveratrol by systematically constructing lipid-surfactant-water phase diagrams using long-chain lipids.

The aim of this work was to develop self-microemulsifying lipid-based formulations of trans-resveratrol in cod liver oil, a long chain lipid, to increase its solubility, dissolution rate and oral bioavailability. Ternary phase diagrams of cod liver oil with surfactant and water as well as pseudo-ternary phase diagrams of the same by mixing cod liver oil (triglyceride) with glycerol monooleate (monoglyeride) were constructed to identify regions where microemulsions were formed. Kolliphor RH 40, Tween 80 and their 1:1-mixtures were evaluated as surfactants. No organic cosolvents were added. It was observed that cod liver oil alone did not form microemulsion with any of the surfactants used, and a 1:1 mixture of cod liver oil and glycerol monooleate was necessary to enable the formation of microemulsion. Among the surfactants, Kolliphor RH 40 provided the maximum microemulsification effect. Several formulations containing 6:4, 1:1, and 4:6 w/w ratios of lipid to surfactant using the 1:1 mixture of cod liver oil and glycerol monooleate as lipid components and Kolliphor RH 40 or its mixture with Tween 80 as surfactants were identified, and trans-resveratrol solubility in these formulations were determined. Drug concentrations used in the formulations were 80% of saturation solubility, and no organic cosolvents were used in any formulations to increase drug solubility or enable emulsification. In vitro dispersion testing in 250 mL of 0.01 N HCl (pH 2) according to the USP method 2 at 50 RPM showed that the formulations rapidly dispersed in aqueous media forming microemulsions and there was no drug precipitation.

The Effect of Process Variables and Binder Concentration on Tabletability of Metformin Hydrochloride and Acetaminophen Granules Produced by Twin Screw Melt Granulation with Different Polymeric Binders.

In twin screw melt granulation, granules are produced by passing mixtures of drug substances and polymeric binders through twin screw extruder such that temperatures are maintained below melting point of drugs but above glass transition of polymers used, whereby the polymers coat surfaces of drug particles and cause their agglomeration into granules. Since various formulation factors, such as binder type and concentration, and processing variables like extrusion temperature, screw configuration, and screw speed, can influence the granulation process, the present investigation was undertaken to study their effects on tabletability of granules produced. Three different types of polymeric binders, Klucel® EXF (hydroxypropyl cellulose), Eudragit® EPO (polyacrylate binder), and Soluplus® (polyvinyl caprolactam-co-vinyl acetate-ethylene glycol graft polymer), were used at 2, 5, and 10% concentrations. Metformin hydrochloride (HCl) (mp: 222°C) and acetaminophen (mp: 169°C) were used as model drugs, and drug-polymer mixtures with metformin HCl were extruded at 180, 160, and 130°C, while those with acetaminophen were extruded at 130 and 110°C. Other process variables included screw configurations: low, medium, and high shear for metformin HCl, and low and medium shear for acetaminophen; feed rates: 20 and 60 g/min; and screw speed of 100 and 300 RPM. Formulation and process variables had significant impact on tabletability. The target tensile strength of ≥2 MPa could be obtained with all polymers and at all processing temperatures when metformin HCl was granulated at 180°C and acetaminophen at 130°C. At other temperatures, the target tensile strength could be achieved at certain specific sets of processing conditions.

Development of Fast-Dissolving Amorphous Solid Dispersion of Itraconazole by Melt Extrusion of its Mixture with Weak Organic Carboxylic Acid and Polymer.

PURPOSE: The purpose of this study was to explore the feasibility of developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion. METHODS: Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon®VA64, was melt extruded at 95°C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH 1.2, followed by a change in pH to 5.5. RESULTS: Despite the high melting point of 168°C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98°C), and physically stable ASD was produced when the formulation was extruded at 95°C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH 1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon®VA64, was formed. CONCLUSIONS: Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water-soluble basic drugs.

Effect of different polysorbates on development of self-microemulsifying drug delivery systems using medium chain lipids.

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80-90%) and the lipid content low (10-20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20 < Tween 40 < Tween 60 < Tween 80 were obtained. Tween 80 had the most profound effect among all surfactants as microemulsions were formed with lipid to surfactant ratios as high as 7:3, which may be attributed to the presence of double bond in its side chain that increased the curvature of surfactant layer. Thus, lipid-surfactant mixtures containing 1:1 mixture of medium chain triglyceride (Captex 355) and monoglyceride (Capmul MCM) and as low as 30% Tween 80 were identified as organic cosolvent-free systems for the preparation of SMEDDS. Formulations with a model drug, probucol, dispersed spontaneously and rapidly upon dilution with water to form microemulsions without any drug precipitation.

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals.

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q10, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q10, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87 mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250 mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200 nm. From all formulations, except that of vitamin K2, >80-90% nutraceuticals dispersed in 5-10 min and there was no precipitation of compounds during the test period of 120 min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.

Continuous Preparation of 1:1 Haloperidol-Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder.

Salts are generally prepared by acid-base reaction in relatively large volumes of organic solvents, followed by crystallization. In this study, the potential for preparing a pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using a twin-screw melt extruder was investigated. The pH-solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation between them was feasible (pHmax 4.8; salt solubility 4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid at the extruder barrel temperature of 60 °C resulted in the formation of a highly crystalline salt. The effects of operating temperature and screw configuration on salt formation were also investigated, and those two were identified as key processing parameters. Salts were also prepared by solution crystallization from ethyl acetate, liquid-assisted grinding, and heat-assisted grinding and compared with those obtained by melt extrusion by using DSC, PXRD, TGA, and optical microscopy. While similar salts were obtained by all methods, both melt extrusion and solution crystallization yielded highly crystalline materials with identical enthalpies of melting. During the pH-solubility study, a salt hydrate form was also identified, which, upon heating, converted to anhydrate similar to that obtained by other methods. There were previous reports of the formation of cocrystals, but not salts, by melt extrusion. 1H NMR and single-crystal X-ray diffraction confirmed that a salt was indeed formed in the present study. The haloperidol-maleic acid salt obtained was nonhygroscopic in the moisture sorption study and converted to the hydrate form only upon mixing with water. Thus, we are reporting for the first time a relatively simple and solvent-free twin-screw melt extrusion method for the preparation of a pharmaceutical salt that provides material comparable to that obtained by solution crystallization and is amenable to continuous manufacturing and easy scale up.

Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying.

PURPOSE: The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation. METHODS: Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes. RESULTS: The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25-40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution. CONCLUSIONS: A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.

Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion, IV: Affinisol™ HPMC HME Polymers.

Most cellulosic polymers cannot be used as carriers for preparing solid dispersion of drugs by hot melt extrusion (HME) due to their high melt viscosity and thermal degradation at high processing temperatures. Three HME-grade hydroxypropyl methylcelluloses, namely Affinisol™ HPMC HME 15 cP, Affinisol™ HPMC HME 100 cP, and Affinisol™ HPMC HME 4 M, have recently been introduced by The Dow Chemical Co. to enable the preparation of solid dispersion at lower and more acceptable processing temperatures. In the present investigation, physicochemical properties of the new polymers relevant to HME were determined and compared with that of Kollidon(®) VA 64. Powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), moisture sorption, rheology, and torque analysis by melt extrusion were applied. PXRD and mDSC showed that the Affinisol™ polymers were amorphous in nature. According to TGA, the onset of degradation for all polymers was >220°C. The Affinisol™ polymers exhibited less hygroscopicity than Kollidon(®) VA 64 and another HPMC polymer, Methocel™ K100LV. The complex viscosity profiles of the Affinisol™ polymers as a function of temperature were similar. The viscosity of the Affinisol™ polymers was highly sensitive to the shear rate applied, and unlike Kollidon(®) VA 64, the viscosity decreased drastically when the angular frequency was increased. Because of the very high shear rate encountered during melt extrusion, Affinisol™ polymers showed capability of being extruded at larger windows of processing temperatures as compared to that of Kollidon(®) VA 64.

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.

Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids.

PURPOSE: To present a novel approach of greatly enhancing aqueous solubility of a model weakly basic drug, haloperidol, by using weak acids that would not form salts with the drug and to attain physically stable form of amorphous drug by drying such aqueous solutions. METHOD: Aqueous solubility of haloperidol in presence of increasing concentrations of four different weak organic acids (malic, tartaric, citric, fumaric) were determined. Several concentrated aqueous solutions with differing drug-to-acid molar ratios were dried in vacuum oven, and dried materials were characterized by DSC, powder XRD, dissolution testing, and stability study. RESULT: Acids were selected such that they would not form salts with haloperidol. Haloperidol solubility increased greatly with increased concentrations of malic, tartaric and citric acids, reaching >300 mg/g of solution. In contrast to the haloperidol HCl aqueous solubility of 4 mg/g, this may be called supersolubilization. Fumaric acid did not cause such solubilization as it had low water solubility. Dried solids formed dispersions of amorphous haloperidol in acids that were either amorphous or partially crystalline. Amorphous haloperidol was physically stable and had better dissolution rate than HCl salt. CONCLUSION: A novel method of drug solubilization in aqueous media by acid-base interaction is presented. Physically stable amorphous systems of drugs may also be prepared by using this organic solvent-free approach.

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.

Challenges, current status and emerging strategies in the development of rapidly dissolving FDM 3D-printed tablets: An overview and commentary.

Since the approval of a 3D-printed tablet by the FDA in 2015 for marketing, there has been a great interest in 3D printing in the pharmaceutical field for the development of personalized and on-demand medications. Among various 3D printing methods explored for the development of oral solid dosage form like tablet, the fused deposition modeling (FDM) 3D-printing, where the drug-polymer mixtures are first converted into filaments by hot melt extrusion (HME) and then the filaments are printed into tablets using 3D printers by applying computer-aided design principles, has emerged as the most attractive option. However, no FDM 3D-printed tablets have yet been marketed as the technology faces many challenges, such as limited availability of pharmaceutical-grade polymers that can be printed into tablets, low drug-polymer miscibility, the need for high temperature for HME and 3D-printing, and slow drug release rates from tablets. These challenges are discussed in this article with a special focus on drug release rates since FDM 3D-printing usually leads to the preparation of slow-release tablets while the rapid release from dosage forms is often desired for optimal therapeutic outcomes of new drug candidates. Pros and cons of various strategies for the development of rapidly dissolving FDM 3D-printed tablets reported in the literature are reviewed. Finally, two case studies on emerging strategies for the development of rapidly dissolving FDM 3D-printed tablets are presented, where one outlines a systematic approach for formulating rapidly dissolving tablets, and the other describes a novel strategy to increase dissolution rates of drugs from FDM 3D-printed tablets, which at the same time can also increase drug-polymer miscibility and printability of tablets and lower processing temperatures. Thus, this overview and commentary discusses various issues involving the formulation of rapidly dissolving FDM 3D-printed tablets and provides guidance for the development of commercially viable products.

Moisture sorption by polymeric excipients commonly used in amorphous solid dispersions and its effect on glass transition temperature: III. Methacrylic acid-methyl methacrylate and related copolymers (Eudragit®).

Moisture sorption by polymeric carriers used in amorphous solid dispersion (ASD) plays a critical role in the physical stability of the dispersed drug as it can increase molecular mobility of drug in ASD by decreasing the glass transition temperatures (Tg) of the drug-polymer system, leading to drug crystallization. The present report describes Part III of a systematic investigation of moisture sorption by different polymers used in ASDs, where the results for four chemically different methacrylic acid-methyl methacrylate and related copolymers, namely, Eudragit® EPO, Eudragit® L100-55, Eudragit® L100, and Eudragit® S100, as the function of relative humidity (RH) are presented. Effects of moisture sorption on Tg of the polymers were also determined. Among the polymers, Eudragit® EPO is the least hygroscopic, having absorbed, for example, 1.3% w/w moisture at 25 °C/60% RH, while the three other polymers absorbed 4.7-7.5% w/w moisture at the same condition. The moisture sorption was relatively lower at 40 °C than that at 25 °C. The apparent Tg of polymers decreased with the increase in moisture content; however, Tg values remained higher than the usual storage temperature of ASD (25 °C) even at high RH, indicating that the effect of moisture sorption on the physical stability of ASD could be minimal when these polymers are used in ASDs.

Improving drug release rate, drug-polymer miscibility, printability and processability of FDM 3D-printed tablets by weak acid-base interaction.

Slow drug release, low drug-polymer miscibility, poor printability of polymers used, and high processing temperature are major challenges in developing FDM 3D-printed tablets. These challenges were addressed in this investigation by having a model basic drug, haloperidol (mp: 151.5 °C), interact with a weak acid, malic acid (mp: 130 °C), during the melt extrusion of formulations into filaments used for 3D-printing. Malic acid was selected as it was previously reported that it did not form any crystalline salt with haloperidol but its addition to aqueous media could greatly increase the solubility of haloperidol from âˆ¼ 1 µg/mL to > 1 g per mL of water by acid-base supersolubilization. Concentrated solutions of haloperidol-malic acid mixtures produced amorphous materials upon drying. It has been observed in the present investigation that similar interaction between haloperidol and malic acid may also occur in the absence of water. Upon heating, haloperidol-malic acid mixtures at 1:1 and 1:2 molar ratios turned amorphous starting at âˆ¼ 50 °C, which is much below the melting point of either component. When Kollidon® VA64, a brittle and non-printable polymer, was used as the polymeric carrier, the acid-base interaction greatly reduced the melt viscosity of haloperidol-malic acid-Kollidon® VA64 ternary mixtures. Consequently, melt extrusion of filaments and printing of tablets using such mixtures could be performed at much lower temperatures than those with haloperidol-Kollidon® VA64 binary mixtures. The filaments containing 15 % and 30 % haloperidol along with malic acid and Kollidon® VA64 could be printed into tablets at relatively low temperatures of 125 and 100 °C, respectively, thus making Kollidon® VA64 not only printable but also doing so at low temperatures. Up to 50 % w/w drug load in filaments was achieved without any crystallization of haloperidol or malic acid. Drug release at pH 2 and 6.8 from printed tablets with 100 % infill was 80 % in < 30 min. Thus, the acid-base interaction can successfully resolve multiple development challenges encountered with FDM 3D-printed tablets.

Development of solid self-emulsifying drug delivery system (SEDDS) I: use of poloxamer 188 as both solidifying and emulsifying agent for lipids.

PURPOSE: To develop solid self-emulsifying drug delivery systems (SEDDS) for lipids using poloxamer 188 as both solidifying and emulsifying agents. METHODS: Mixtures of various lipids with poloxamer 188 and PEG 8000 were prepared at ~75°C. The molten mixtures, with and without dissolved drugs (fenofibrate and probucol), were then cooled to room temperature. When solids formed, they were characterized by powder XRD, DSC, microscopy using cross-polarization and confocal fluorescence techniques, dispersion test in water and particle size analysis of dispersions. RESULTS: When mixed with poloxamer 188 or PEG 8000, lipids consisting of monoesters of fatty acids with glycerol or propylene glycol formed solid systems, but not di- and tri-esters, which showed phase separation. Added to water, the solid systems containing poloxamer 188 started to disperse in water forming oil globules of 200-600 nm. No emulsification of lipids was observed from solids containing PEG 8000, indicating that the surfactant property of poloxamer 188 was responsible for emulsification. Powder XRD, DSC and microscopic examination revealed that poloxamer 188 and PEG 8000 maintained their crystallinity in solid systems, while the lipids were interspersed in between crystalline regions. The drug remained solubilized in the lipid phase. CONCLUSIONS: A novel solid SEDDS is developed where the drug can be solubilized in liquid lipids and then the lipidic solution can be converted to solid mass by dispersing into the microstructure of poloxamer 188.

A comparative evaluation of mono-, di- and triglyceride of medium chain fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in pharmaceutical dosage form development.

PURPOSE: To compare physiochemical properties of mono-, di- and triglycerides of medium chain fatty acids for development of oral pharmaceutical dosage forms of poorly water-soluble drugs using phase diagrams, drug solubility, and drug dispersion experiments. METHODS: Phase diagrams were prepared using a monoglyceride (glycerol monocaprylocaprate: Capmul MCM® EP), a diglyceride (glycerol dicaprylate) and two triglycerides (glycerol tricaprylate: Captex 8000®; caprylic/capric triglycerides: Captex 355 EP/NF®) in combination with a common surfactant (PEG-35 castor oil: Cremophor EL®) and water. Psuedoternary phase diagrams using mixtures of monoglyceride with either diglyceride or triglyceride were constructed to determine any potential advantage of using lipid mixtures. RESULT: The monoglyceride gave microemulsion (clear or translucent liquid) and emulsion phases, whereas di- and triglycerides exhibited an additional gel phase. Among individual mono-, di- and triglycerides, the oil-in-water microemulsion region was the largest for the diglyceride. Gel phase region within diglyceride and triglyceride phase diagrams could be practically eliminated and microemulsion regions expanded by mixing monoglyceride with di- or tri-glycerides (1:1). Addition of a model drug, danazol, had no effect on particle sizes of microemulsions formed. Dispersion of drug in aqueous media from mixtures of mono- and diglyceride or mono- and triglyceride was superior to individual lipids. CONCLUSION: Systematic study on comparison of mono-, di- and triglyceride of medium chain fatty acids will help formulators select components for optimal lipid-based formulation.