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.

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.

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.

Moisture Sorption by Polymeric Excipients Commonly Used in Amorphous Solid Dispersions and its Effect on Glass Transition Temperature: II. Cellulosic Polymers.

Moisture sorption by polymeric carriers used for the development of amorphous solid dispersions (ASDs) plays a critical role in the physical stability of dispersed drugs since moisture may decrease glass transition temperature (Tg) and thereby increase molecular mobility of drugs leading to their crystallization. To assist the selection of appropriate polymers for ASDs, we conducted moisture sorption by five types of cellulosic polymers, namely, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), and ethyl cellulose (EC), as functions of relative humidity (10 to 90% RH) and temperature (25 and 40 °C). The moisture sorption was in the order of HPC>HPMC>HPMCP>HPMCAS>EC, and there was no significant effect of the molecular weights of polymers on moisture uptake. There was also less moisture sorption at 40 °C than that at 25 °C. Glass transition temperatures (Tg) of the polymers decreased with the increase in moisture content. However, the plasticizing effect by moisture on HPC could not be determined fully since, despite being amorphous, there were very little baseline shifts in DSC scans. There was also very shallow baseline shift for HPMC at >1% moisture content. In contrast, Tg of HPMCAS and HPMCP decreased in general agreement with the Gordon-Taylor/Kelley-Bueche equation, and EC was semicrystalline having both Tg and melting endotherm, with only minor effect of moisture on Tg. The results of the present investigation would lead to a systematic selection of polymeric carriers for ASDs.

Moisture sorption by polymeric excipients commonly used in amorphous solid dispersion and its effect on glass transition temperature: I. Polyvinylpyrrolidone and related copolymers.

Moisture plays a critical role in the stability of amorphous solid dispersions (ASD) as it can lower the glass transition temperature (Tg) and thereby increase molecular mobility resulting in drug crystallization. A systematic study on moisture sorption by four polyvinylpyrrolidone (PVP) having different molecular weights (Kollidon® 12, 17, 30, and 90) and two related copolymers (Kollidon® VA64; Soluplus®) was conducted at 25 and 40 °C as a function of relative humidity to determine effects of absorbed moisture on Tg and potential stability of ASDs. A VTI dynamic moisture sorption analyzer was used, where experimental conditions were first established such that equilibrium was reached and there was no significant hysteresis loop between sorption and desorption isotherms. The PVPs had identical moisture sorption profiles and were highly hygroscopic, reaching 22-24% and 41-42% w/w moisture at 25 °C/60% RH and 25 °C/80% RH, respectively. Kollidon® VA64 and Soluplus® were relatively less hygroscopic, reaching, respectively, about half and one-fourth the moisture content of PVPs at 25 °C/60% RH. Moisture sorption at 40 °C was relatively lower than that at 25 °C. The high moisture sorption drastically decreased Tg of polymers, which roughly agreed with theoretical calculations based on the Gordon-Taylor/Kelley-Bueche equation, although deviation occurred, possibly due to hydrogen bonding between polymer and moisture.

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 Fully Redispersible Dried Nanocrystals by Using Sucrose Laurate as Stabilizer for Increasing Surface Area and Dissolution Rate of Poorly Water-Soluble Drugs.

There is much interest in converting poorly water-soluble drugs into nanocrystals as they provide extremely high surface area that increases dissolution rate and oral bioavailability. However, nanocrystals are prepared as aqueous suspensions, and once the suspensions are dried for development of solid dosage forms, the nanocrystals agglomerate as large particles to reduce the excess surface energy. For successful development of drug products, it is essential that any agglomeration is reversible, and the dried nanocrystals regain original particle sizes after redispersion in aqueous media. We have established that sucrose laurate serves as a superb stabilizer to ensure complete redispersion of dried nanocrystals in aqueous media with mild agitation. Nanocrystals (150-300 nm) of three neutral drugs (fenofibrate, danazol and probucol) were produced with sucrose laurate by media milling, and suspensions were dried by tray drying under vacuum, spray drying, and lyophilization. Dried solids and their tablets redispersed into original particle sizes spontaneously. Preliminary studies showed that sucrose laurate can also redisperse acidic and basic drugs, indicating its versatile application. Fatty acid ester of another disaccharide, lactose laurate, also performed like sucrose laurate. Thus, we have developed a method of retaining high dissolution rate and, by implication, high bioavailability of nanocrystals from solid formulations.

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 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.

Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle.

Some of the major issues with the development of FDM 3D printed tablets are slow drug release, lack of drug-polymer miscibility, high processing temperature, and poor printability. In this investigation, these issues were addressed by using a novel physicochemical principle called acid-base supersolubilization (ABS) previously developed in our laboratory. The aqueous solubility of a basic drug, haloperidol, was increased to ~300 mg/g of solution by adding glutaric acid, and, upon drying, the concentrated solutions produced amorphous materials. Similar amorphous systems could also be produced by heating haloperidol-glutaric acid mixtures. Filaments for 3D printing were prepared by melt extrusion of formulations containing 15% w/w haloperidol and 10.5% glutaric acid (1:2 M ratio) along with 74.5% polymers, such as Kollidon® VA64 alone or its mixtures with Affinisol™ 15cP. Filaments could be extruded and printed at low temperatures of 115 and 120 °C, respectively. Haloperidol was fully miscible in the formulations because of the acid-base interaction and formed amorphous systems even at higher drug loads. Although filaments of haloperidol-Kollidon® VA64 mixtures by themselves cannot be printed, the printability of formulation improved such that those containing glutaric acid were printable. Drug release rates from the formulations at pH 2 and 6.8 were rapid and complete.

Aqueous Dissolution and Dispersion Behavior of Polyvinylpyrrolidone Vinyl Acetate-based Amorphous Solid Dispersion of Ritonavir Prepared by Hot-Melt Extrusion with and without Added Surfactants.

In this study, the lack of complete drug release from amorphous solid dispersions (ASDs), as observed in most published reports, was investigated. ASDs with 20% ritonavir were prepared by HME using polyvinylpyrrolidone vinyl acetate (PVPVA) alone and in combination with 10% poloxamer 407 or Span 20 as carriers. It was established by the film casting technique that ritonavir was molecularly dispersed in formulations, and accelerated stability testing confirmed that extrudates were physically stable. Dissolution of ASDs (100-mg ritonavir equivalent) was performed in 250 mL 0.01 N HCl (pH 2), pH 6.8 phosphate buffer and FeSSIF-V2. Drug concentrations were measured by filtration through 0.45-µm pores and in unfiltered media; the latter gave total amounts of drug present in dissolution media, both as solution and dispersion. Because of low solubility, ritonavir did not dissolve completely in aqueous media. Rather, it formed supersaturated solutions, and the excess drug dispersed in the oily amorphous form with low particle sizes that could crystallize with time. Due to higher drug solubility, the dissolved drug in FeSSIF-V2 was much higher than that in the phosphate buffer. Complete drug release could be observed by accounting for drug both in solution and as phase-separated dispersion. Thus, the present study provides a complete picture of in vitro drug dissolution and dispersion from ASDs.

Conversion of α-lactose monohydrate to anhydrous form with superior tabletability by twin-screw extrusion at elevated temperature.

The purpose of this study was to improve tabletability (tensile strength versus compaction pressure) of α-lactose monohydrate by twin screw extrusion (TSE) near its dehydration temperature but below its melting point. When extruded at 150 and 160 °C, α-lactose monohydrate converted completely to α-lactose anhydrous that was mostly crystalline and only partially amorphous; the latter was indicated by glass transition observed in DSC scans. Tabletability of the material thus obtained by TSE was superior to anhydrous lactose available commercially or produced by hot air oven drying at 160 °C. The superior tabletability was attributed to the partial conversion to amorphous lactose. When samples of anhydrous lactose powders obtained by TSE or oven drying were exposed to 25 °C/60% RH and 40 °C/75% RH, they reverted to the monohydrate with decreased tabletability. However, when anhydrous lactose powders produced by TSE were first compressed into tablets with high tensile strength and then exposed to similar stability testing conditions, there was no decrease in the tensile strength of tablets. Rather, it further increased, possibly due to the interaction of the amorphous fraction of lactose with moisture. Thus, TSE not only increased tabletability of α-lactose monohydrate, the compressed tablets remained intact and hard during shelf-life. These results demonstrate that a new modified anhydrous lactose may be produced by TSE that has better tabletability and superior physical stability than α-lactose monohydrate and the commercially available anhydrous lactose.

Evaluation of Cytotoxicity of Self-Emulsifying Formulations Containing Long-Chain Lipids Using Caco-2 Cell Model: Superior Safety Profile Compared to Medium-Chain Lipids.

Medium-chain (MC) and long-chain (LC) lipids are used for development of self-emulsifying drug delivery systems (SEDDS). MC lipids are often preferred because of their ability to form stable microemulsions with relatively high drug solubilization capacity. On the other hand, LC lipids could be more biocompatible as most endogenous and dietary lipids are LC glycerides. They also maintain high drug solubilization capacity after digestion. The present study was undertaken to determine the cytotoxicity of LC lipids and their formulations on Caco-2 cells of 1-day, 5-day, and 21-day maturity. The results were compared with the cytotoxicity profiles of MC lipids reported previously from our laboratory. The cell viability and cell membrane integrity were, respectively, determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the lactate dehydrogenase assay. The cytotoxicity was partially due to lipid surfactant-induced membrane rupture, and it was influenced by cell maturity and formulation composition. The lipid-surfactant combinations showed greater tolerance than surfactants alone, and LC-SEDDS were well-tolerated at almost 10-fold higher concentration than corresponding MC-SEDDS. Furthermore, the cytotoxicity of digestion end products of both LC and MC triglycerides in the presence of 3 mM sodium taurocholate was compared on 21-day Caco-2 cultures by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The LC lipid formulations showed better tolerance than MC lipid formulations after digestion. Thus, although MC and LC lipids are well-tolerated at doses normally administered to humans, LC lipids show much better safety than MC lipids in a cell-culture model.

Development of 3D Printed Tablets by Fused Deposition Modeling Using Polyvinyl Alcohol as Polymeric Matrix for Rapid Drug Release.

In this study, the processability of polyvinyl alcohol (PVA), a water-soluble polymer, into melt-extruded filaments and then into 3D printed tablets by fused deposition modeling was studied. PVA is semicrystalline with Tg and m.p. of ~45°C and ~190°C, respectively. After screening several plasticizers, sorbitol was selected to enhance melt extrudability of PVA. Carvedilol and haloperidol, 2 basic compounds with pH-dependent solubility, were used as model drugs. Miscibility of the drugs with PVA, with and without added sorbitol as plasticizer, was also tested to determine whether any amorphous solid dispersion was formed that would facilitate rapid and pH-independent dissolution. Finally, the drug release from physical mixtures, crushed extrudates, and printed tablets were determined. Owing to high m.p. and high melt viscosity of PVA, filaments containing 10% and 20% drug required 180°C-190°C for extrusion, which could be reduced to ~150°C by adding 10% sorbitol. The printing temperature of 210°C was, however, required. Miscibility of carvedilol and haloperidol with PVA were, respectively, ~20% and <10%. PVA provided complete drug release from 3D printed tablets with 10% and 20% carvedilol and 60% infill in ~45 min at both pH 2 and 6.8. However, despite relatively rapid dissolution rate, high processing temperature and limited drug-polymer miscibility could be potential development issues with PVA.

Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion III: Tableting of Extrudates and Drug Release From Tablets.

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has gained popularity as a carrier for amorphous solid dispersion because of its ability to maintain drugs in supersaturated state after dissolution in aqueous media. In part I and II of this series of articles, we have demonstrated that amorphous solid dispersions containing HPMCAS may be prepared using surfactants as plasticizers to reduce processing temperature (Solanki et al., J Pharm Sci. 2019; 108:1453-65), where surfactants also increase dissolution rate and degree of supersaturation (Solanki et al., J Pharm Sci. 2019; 108: 3063-73). The present investigation was undertaken to develop melt extrudates of itraconazole-HPMCAS and itraconazole-surfactant-HPMCAS mixtures into tablets having tensile strength ≥2 MPa, where poloxamer 407 and d-α-tocopherol polyethylene glycol 1000 succinate were used as surfactants. Milled filaments were sieved to collect <212-µm particles, which were then compressed into tablets with different excipients (silicified microcrystalline cellulose [MCC], Avicel PH-102, dicalcium phosphate, lactose, and Starch 1500). Initial screening of various diluents showed that only silicified MCC and Avicel PH-102 could provide the target tensile strength of ≥2 MPa. Tabletability (tensile strength vs. compaction pressure), compressibility (porosity vs. compaction pressure), and compactibility (tensile strength vs. porosity) were then studied for tablet formulations. The desired tensile strength could be obtained at the diluent level of 50%-70%, where silicified MCC provided better hardness than Avicel PH-102. Tablets disintegrated in <2 min, and drug release from tablets was comparable to that of milled filaments.

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.

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, H3PO4, or NaOH to adjust pH) were performed on phosphate-buffered (0.12­0.15 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 (Ksp2:1 = [DsH+]2[HPO42-]) was determined from data in the pH 4-9 region. The free base of desipramine was prepared and used to determine the Ksp1:1 ([DsH+][H2PO4-]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S0, and the 1:1 drug-chloride solubility product, KspDsHCl = [DsH+][Cl-]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pHmax 8.0. In phosphate-containing solutions, pHmax was indicated at higher pH (8.8-9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pHmax in saturated phosphate­containing 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 < 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.