Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH

Since there are conflicting reports in the literature on solubility and dissolution advantages of cocrystals over free forms, we systematically studied solubility and intrinsic dissolution rates of a weakly basic drug, ketoconazole, and its cocrystals with fumaric acid and succinic acid as functions of pH to determine what advantages cocrystals provide. pH-solubility profiles were determined in two different ways: one by lowering pH of ketoconazole aqueous suspensions using HCl, fumaric acid and succinic acid, and the other by adjusting pH of cocrystal suspensions using respective coformer acids or NaOH. Similar pH-solubility profiles were obtained whether free base or cocrystals were used as starting materials to determine solubility. With the addition of fumaric and succinic acids to aqueous suspensions of free base to lower pH, the maximum solubility (pHmax) was reached at pH ~3.5-4.0, below which the solubility decreased and cocrystals formed. The solubility, however, continued increasing when HCl was added to ketoconazole suspension as no cocrystal or salt was formed. During determination of cocrystal solubility, a conversion to free base was observed when pH was raised above pHmax. Thus, pH-solubility profiles of cocrystals resembled solubility profiles commonly encountered with salts. Above pHmax, both free base and cocrystal had similar solubility under identical pH conditions; the solubility of cocrystal was higher only if the pH differed. In contrast, intrinsic dissolution rates of cocrystals at pH>pHmax under identical bulk pH were much higher than that of free ketoconazole since cocrystals had lower microenvironmental pH at the dissolving surface, where the solubility was high. Thus, cocrystals of basic drugs can potentially provide higher dissolution rates under intestinal pH conditions

Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - I: Polyvinylpyrrolidone and related polymers

Polymers are essential components of melt extruded products. The objective of the present study was to generate physicochemical data of polyvinylpyrrolidone-based polymers and copolymers that are used in hot melt extrusion (HME). This study focused on investigating the importance of viscoelasticity for predicting HME processing conditions. Powder X-ray diffraction (XRD) patterns of polymers were recorded to determine the physical nature of the polymers. Differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA) were carried out to determine their glass transition temperature (Tg) and weight loss due to degradation (Td), respectively. Rheological studies were conducted to quantitate storage modulus (G´), loss modulus (G˝), tan δ and complex viscosity (η) of the polymers at various temperatures. Powder XRD analyses showed that all polymers were amorphous in nature, with distinct single or dual halos. DSC showed that the amorphous polymers had single Tg values. The conversion of the polymers, from solid to liquid forms, with increasing temperature was established by the tan δ = 1 values. The overall complex viscosity for all polymers decreased with increasing temperature. The complex viscosity of one of the polymers, Soluplus®, was correlated using torque analysis through HME to establish an extrudable temperature range. The results are expected to assist in the selection of polyvinylpyrrolidone-based polymers for HME. Once the appropriate polymers are selected, further studies may be carried out using drugs, plasticizers and, so on, to optimize processing conditions

Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - III: Polymethacrylates and polymethacrylic acid based polymers

Polymers are a major part of final medicinal drug products prepared by hot melt extrusion (HME). Therefore it is necessary to understand their behavior when subjected to heat and mechanical stresses during the development of the HME processes. The aim of this work was to generate a database of the physicochemical properties for polymethacrylates and polymethacrylic acid based polymers relevant to HME. All six polymers tested were amorphous and had < 2% moisture. In differential scanning calorimetric (DSC) studies, the three homo block copolymers, Eudragit® E PO, Eudragit® RL PO and Eudragit® RS PO, had glass transition temperatures (Tg) of 57°C, 63°C and 64°C, respectively, and thermogravimetric analysis (TGA) showed weight loss due to thermal degradation at 250°C, 166°C and 170°C, respectively. Thermomechanical analysis was carried out to investigate the rheological properties of the polymers predicting that the melt extrusion ranges of Eudragit® E PO, Eudragit® RL PO and Eudragit® RS PO would be 127-150, 165-170 and 142-167°C, respectively. In contrast, the hetero block copolymers Eudragit® L 100, Eudragit® S 100 and Eudragit® L 100-55 had Tg values of 195, 173 and 111°C, respectively. Onsets of their degradation, as measured by TGA, were in the range of 173 to176°C. The predicted HME processing temperatures of Eudragit® L 100, Eudragit® S 100 and Eudragit® L 100-55 were greater than 200°C and therefore these polymers cannot be processed by themselves without the addition of plasticizers

Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates

Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH &gt; 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH &lt; 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.This is the peer-reviewed version of the following article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. [https://doi.org/10.1016/j.ejps.2019.03.014]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2926

Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - II: Cellulosic polymers

The purpose of this study was to determine the thermal and viscoelastic properties of cellulosic polymers that may have potential for use in hot melt extrusion (HME). Cellulose ethers of different molecular weight (MW) with varied degrees of substitution and differences in substituted groups were analyzed using modulated differential scanning calorimetry (MDSC), thermogravimetric analysis (TGA) and oscillatory rheometry. The results indicated that the glass transition temperature (Tg) and viscoelastic characteristics of polymers appear to depend on their chain length, molecular weight (MW), and degree and type of substitutions in the main chain. In general, an increase in the chain length or MW increased Tg, as well as, the viscosity (HPMC, MW10000 < MW 25000 < MW 150000 Da). Additionally, substitutions with bulkier groups decreased both the Tg and the viscosity of the polymer. Most of the cellulosic polymers had high viscosity between their Tg and degradation temperature (Td), and could not be extruded by themselves. The thermal properties in combination with polymer viscosity at different temperatures may assist formulating scientists in determining the processability when using HME

Development of Solid SEDDS, II: application of Acconon® C-44 and Gelucire® 44/14 as solidifying agents for self-emulsifying drug delivery systems of medium chain triglyceride.

Self-emulsifying drug delivery systems (SEDDS) are usually isotropic liquids consisting of drugs, lipids, surfactants and/or co-surfactants that spontaneously form fine oil-in-water emulsions in contact with water. Since a solid dosage form has better patient acceptance than a liquid, it was investigated whether liquid SEDDS containing medium-chain lipids (mono- or tri-glycerides) may be converted to solids or semisolids using lauroyl polyoxyl glycerides (Acconon® C-44, ABITEC, and Gelucire® 44/14, Gattefosse) as solidifying agents. Acconon® C-44 and Gelucire® 44/14 were melted at 65EC. The liquid lipids or the liquid lipidsurfactant mixtures, with and without dissolved drug (probucol), were mixed with the melts, and the hot liquid solutions were filled into hard gelatin capsules. The solutions solidified inside the capsules when cooled to room temperature. Acconon® C-44 and Gelucire® 44/14 had a greater propensity for solidifying the triglyceride of medium chain fatty acids (Captex® 355, ABITEC) rather than the monoglyceride. Powder XRD, DSC and microscopic analyses indicated that the lauroyl polyoxyl glycerides crystallized at room temperature, while the lipid or the lipid-surfactant mixtures present in the formulations remained interspersed in between solids as a separate liquid phase. The drug remained dissolved in the liquid phase and there was no crystallization of the drug. Although Acconon® C-44 and Gelucire® 44/14 are themselves surface active, the dispersion testing using the USP apparatus II at 50 rpm and 37EC using 250 ml of 0.01N HCl as the dispersion medium showed that a second surfactant (Cremophor® EL®, BASF) was required in the solid formulation to maximize drug release and dispersion. Formulations containing 1:1 and 3:1 w/w ratios of Captex® 355 and Cremophor® EL produced lipid particles in the range of 200 to 450 nm. Thus, a novel approach of preparing solid SEDDS resulting in submicron emulsions with particle size <500nm is presented

Development of Solid SEDDS, II: application of Acconon® C-44 and Gelucire® 44/14 as solidifying agents for self-emulsifying drug delivery systems of medium chain triglyceride.

Self-emulsifying drug delivery systems (SEDDS) are usually isotropic liquids consisting of drugs, lipids, surfactants and/or co-surfactants that spontaneously form fine oil-in-water emulsions in contact with water. Since a solid dosage form has better patient acceptance than a liquid, it was investigated whether liquid SEDDS containing medium-chain lipids (mono- or tri-glycerides) may be converted to solids or semisolids using lauroyl polyoxyl glycerides (Acconon® C-44, ABITEC, and Gelucire® 44/14, Gattefosse) as solidifying agents. Acconon® C-44 and Gelucire® 44/14 were melted at 65EC. The liquid lipids or the liquid lipidsurfactant mixtures, with and without dissolved drug (probucol), were mixed with the melts, and the hot liquid solutions were filled into hard gelatin capsules. The solutions solidified inside the capsules when cooled to room temperature. Acconon® C-44 and Gelucire® 44/14 had a greater propensity for solidifying the triglyceride of medium chain fatty acids (Captex® 355, ABITEC) rather than the monoglyceride. Powder XRD, DSC and microscopic analyses indicated that the lauroyl polyoxyl glycerides crystallized at room temperature, while the lipid or the lipid-surfactant mixtures present in the formulations remained interspersed in between solids as a separate liquid phase. The drug remained dissolved in the liquid phase and there was no crystallization of the drug. Although Acconon® C-44 and Gelucire® 44/14 are themselves surface active, the dispersion testing using the USP apparatus II at 50 rpm and 37EC using 250 ml of 0.01N HCl as the dispersion medium showed that a second surfactant (Cremophor® EL®, BASF) was required in the solid formulation to maximize drug release and dispersion. Formulations containing 1:1 and 3:1 w/w ratios of Captex® 355 and Cremophor® EL produced lipid particles in the range of 200 to 450 nm. Thus, a novel approach of preparing solid SEDDS resulting in submicron emulsions with particle size <500nm is presented

Effect of Difference in Fatty Acid Chain Lengths of Medium- Chain Lipids on Lipid/Surfactant/Water Phase Diagrams and Drug Solubility

Lipids consisting of medium chain fatty acids are commonly used in the development of lipid-based selfemulsifying and self-microemulsifying drug delivery systems. However, no systematic approach to selecting one lipid over another has been reported in the literature. In this study, propylene glycol (PG) monoester (PG monocaprylate, Capmul PG-8®) and PG diester (PG dicaprylocaprate, Captex 200P®) of C8-fatty acids were compared with PG monoester (PG monolaurate, Capmul PG-12®) and PG diester (PG dilaurate, Capmul PG-2L®) of C12-fatty acids with respect to their phase diagrams, and especially for their ability to form microemulsions in the presence of a common surfactant, Cremophor EL®, and water. The solubility of two model drugs, danazol and probucol, in the lipids and lipid/surfactant mixtures were also compared. The effect of the chain length of medium-chain fatty acids (C8 versus C12) on the phase diagrams of the lipids was minimal. Both shorter and longer chain lipids formed essentially similar microemulsion and emulsion regions in the presence of Cremophor EL® and water, although the C12-fatty acid esters formed larger gel regions in the phase diagrams than the C8-fatty acid esters. When monoesters were mixed with their respective diesters at 1:1 ratios, larger microemulsion regions with lower lipid particle sizes were observed compared to those obtained with individual lipids alone. While the solubility of both danazol and probucol increased greatly in all lipids studied, compared to their aqueous solubility, the solubility in C12-fatty acid esters was found to be lower than in C8-fatty acid esters when the lipids were used alone. This difference in solubility due to the difference in fatty acid chain length, practically disappeared when the lipids were combined with the surfactant

In Vitro Dispersion Test Can Serve as a Predictive Method for Assessing Performance of Lipid-based Drug Delivery Systems

A relatively simple in vitro dispersion test using the USP Dissolution Apparatus II with 250 mL of dispersion fluid (0.01M HCl) at 37°C and the rotation speed 50 RPM was used to assess the performance of lipid-based formulations. Solutions of probucol in mixtures of the surfactant Cremophor EL with four different medium chain lipids (glycerol monocaprylocaprate, Capmul MCM EP; glycerol dicaprylate; glycerol tricaprylate, Captex 8000 EP/NF; caprylic/capric triglyceride, Captex 355 EP/NF) were formulated and filled in Number 00 hard gelatin capsules (~1 g/capsule) for dispersion testing.. Drug concentration in the dispersion fluid and the particle size of the dispersed phase as a function of time were measured without and with filtration through filters of 0.45 micron pore size. All lipid/surfactant mixtures used dispersed (≥80%) in &lt;1 h, indicating their suitability for the development of immediate-release formulations. The particle size of unfiltered samples indicated whether microemulsion (&lt;250 nm), very fine emulsion (250-1000 nm) or emulsion with relative larger sizes (&gt;1000 nm) were formed. The dispersion test developed is capable of screening different lipid-based formulations for in vitro performance. Justification is also provided for using the dispersion test as a predictive method for assessing in vivo performance of such formulations