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The focus of the present work was to develop co-amorphous dispersion (CAD) formulations of tacrolimus (TAC) using sucrose acetate isobutyrate as a carrier, evaluate by in vitro and in vivo methods and compare its performance with hydroxypropyl methylcellulose (HPMC) based amorphous solid dispersion (ASD) formulation. CAD and ASD formulations were prepared by solvent evaporation method followed by characterization by Fourier transformed infrared spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dissolution, stability, and pharmacokinetics. XRPD and DSC indicated amorphous phase transformation of the drug in the CAD and ASD formulations, and dissolved more than 85% of the drug in 90 min. No drug crystallization was observed in the thermogram and diffractogram of the formulations after storage at 25 °C/60% RH and 40 °C/75% RH. No significant change in the dissolution profile was observed after and before storage. SAIB-based CAD and HPMC-based ASD formulations were bioequivalent as they met 90% confidence of 90–11.1% for Cmax and AUC. The CAD and ASD formulations exhibited Cmax and AUC 1.7–1.8 and 1.5–1.8 folds of tablet formulations containing the drug's crystalline phase. In conclusion, the stability, dissolution, and pharmacokinetic performance of SAIB-based CAD and HPMC-based ASD formulations were similar, and thus clinical performance would be similar. [ABSTRACT FROM AUTHOR]

Palatability of a formulation is one of the primary requirements for therapeutic compliance in children. Clindamycin (CLN) often prescribed to children to treat various infections. However, it has a bitter taste and bad smell. The focus of the present investigation was to develop salt of CLN with a commonly used sweetener such as cyclamic acid (CYA) to improve the palatability. The salt forms were prepared by solubilization crystallization method and characterized by Fourier transformed infrared (FTIR), Near infrared (NIR), Raman, X-ray powder diffraction, scanning electron microscopy, solubility, dissolution, and solid-state physical and chemical stability at 25 °C/60% RH and 40 °C/75% RH for 1 month and 60 °C for 2 weeks. Spectroscopic and diffraction data indicated the formation of a new solid phase, which was different from hydrochloride salt of CLN. Shape of crystal was rectangular prism. Stoichiometric ratio between CLN and CYA in the new salt CLN-CYA was 1:1 and its melting point was 85.6 °C. There was a 2.4-fold reduction in solubility of CLN-CYA at pH 4 compared with CLN-HCl. Moreover, the dissolution rate and extent were similar between the two salts and meeting USP requirement of 85% dissolution in 30 min. Salt was physically and chemically stable at 60 °C, 25 °C/60% RH, and 40 °C/75% RH conditions but hygroscopic at high humidity condition. In conclusion, new salt will provide a new avenue for the development of a palatable formulation of CLN. [ABSTRACT FROM AUTHOR]

The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 °C for two weeks, 25 °C/60%RH, 40 °C/75%RH and 40 °C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 °C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to evaluate the effect of some processing parameters on the release of lipid formulation from a tablet dosage form. A 17-run, face-centered cubic design was employed to evaluate the effect of colloidal silicates (X 1), magnesium stearate mixing time (X 2), and compression force (X 3) on flow, hardness, and dissolution of Coenzyme Q10 (CoQ10) lipid formulation from a tablet dosage form. The optimized formulation was subsequently subjected to a short-term accelerated stability study. All preparations had a flowability index values ranging from 77 to 90. The cumulative percent of CoQ10 released within 8h (Y 5) ranged from 40.6% to 90% and was expressed by the following polynomial equation: . When stored at 4°C, dissolution rates were retained for up to 3 months. Storage at higher temperatures, however, accelerated lipid release and caused leakage, and loss of hardness. Processing parameters have a profound effect on the release of lipid formulations from their solid carriers. While optimized controlled release formulations could be attained, further considerations should be made to prepare “liquisolids” that are physically stable at higher storage temperatures. [Copyright &y& Elsevier]

An isocratic reversed-phase high-performance liquid chromatographic method was developed and validated for the determination of ranitidine HCl in syrup. The samples were analyzed by high-performance liquid chromatography (HPLC). Chromatographic separation was achieved on a C 18 column using an acetonitrile–aqueous phosphate buffer (20:80, v/v) elution, buffer being 10 mM disodium hydrogen phosphate brought to pH 7.1 with sodium hydroxide (0.1 N). Validation steps involved measurement of selectivity, accuracy, and precision under conditions of repeatability, reproducibility, sensitivity, and robustness. The lower limit of quantification was 10µg/mL. The validated method has been demonstrated to be reliable for the determination of ranitidine HCl and its related compound C. Stress degradation studies included exposing ranitidine HCl powder and Zantac syrup to acid, alkali, oxidation, and accelerated temperature of 50 °C for 24 hrs and photolysis for 8 hrs. The peaks of degraded products were well resolved from the drug peak. The validation of this method indicated that it could be effectively used to monitor the stability of ranitidine HCl syrup. [ABSTRACT FROM AUTHOR]

Coronavirus (COVID-19) outbreak from Wuhan, Hubei province in China and spread out all over the World. In this work, a new mathematical model is proposed. The model consists the system of ODEs. The developed model describes the transmission pathways by employing non constant transmission rates with respect to the conditions of environment and epidemiology. There are many mathematical models purposed by many scientists. In this model, " α E " and " α I ", transmission coefficients of the exposed cases to susceptible and infectious cases to susceptible respectively, are included. " δ " as a governmental action and restriction against the spread of coronavirus is also introduced. The RK method of order four (RK4) is employed to solve the model equations. The results are presented for four countries i.e., Pakistan, Italy, Japan, and Spain etc. The parametric study is also performed to validate the proposed model. [ABSTRACT FROM AUTHOR]

The physicochemical properties and enzymatic stability of esters of phenylephrone, synthesized on the basis of the chemical delivery system (CDS) concept, were studied as a new class of mydriatic agents. Potentiometrically determined ionization constants (pKa) of the novel compounds were in the range 7.19–7.21. The three esters of phenylephrone (isovaleryl, phenylacetyl, and pivalyl) were more lipophilic than phenylephrone as indicated by n-octanol/pH 7.4 buffer partition coefficients (log Papp) and the chromatographic capacity factors (log k′). The chemical stability of the esters of phenylephrone was evaluated in hydrochloric acid, citrate, and phosphate buffers (with pH ranging between 2.0 and 8.0), and the enzymatic hydrolysis in rat and human plasma. The samples were analyzed using HPLC assay procedures. The phenylephrone esters were found to undergo comparatively slow hydrolytic degradation in buffer with pH 3.0 and 4.0, with half-lives ranging from 1136 to 1980 hr at 37°C. The novel esters were readily hydrolyzed in human plasma with half-lives ranging between 16.2 and 47.8 min. The hydrolytic degradation rates were higher in rat plasma than in human plasma, in which the half-lives were in the range of 9.8–38.3 min. In the present investigations, only phenylephrone, not the active species phenylephrine, was detected. Among the esters studied, isovaleryl ester was the most labile. Pivalyl ester, having a tertiary carbon, showed relatively high resistance to chemical and enzymatic hydrolysis because of the steric hindrance, followed by phenyl and isovaleryl esters. The results suggest that the duration of action of the phenylephrone CDS can be controlled with proper chemical manipulations. [ABSTRACT FROM AUTHOR]

A novel and simple strategy was designed for the synthesis of an unmodified gum arabic (GA) and acrylic acid (AA) based polymer hydrogels using Fe3+ as a physical cross-linking agent. The hydrogels showed a high mechanical strength, self-sustainability and self-healing ability, which depends on the content of GA and Fe3+ in the composition. The fracture stress increased from 0.23 to 0.841 MPa and a decrease in self-healing from 53 to 34% was observed by increasing the GA amount from 12 to 50% respectively. The self-healing performance of the hydrogels enhanced with the existence of the Fe3+ amount on the interface. Therefore, the 3% addition of Fe3+, increased the self-healing ability of up to 70%. Furthermore, the hydrogels also showed an excellent fatigue resistance up to 20 cycles without any rapture and can beard a load of 2.5 kg for a very long time. After 4 min of resting time, the percent recovery in dissipated energy reaching a high value of 95%, indicating the excellent fatigue resistance performance of the hydrogels. The hydrogels contain 3–5% of water at normal conditions and confirm its environmental stability. This work provides a new direction for the synthesis of unmodified GA based physically cross-linked polymer hydrogels systems and can be applied in bioengineering and robotic science in the future. • Successful synthesis of GA and AA based hydrogels using Fe3+ as a physical cross-linker • GA increased the mechanical strength and maintained the integrity of hydrogels. • The self-healing ability was strongly depends on the Fe3+ at the interface of cut pieces. • The elastic character of hydrogels increased with the number of cycles in fatigue test. • The hydrogels can beard a load of 2.5 kg for a long time proving its high strength. [ABSTRACT FROM AUTHOR]

The focus of present work was to synthesize prodrugs of dolutegravir (DTG) for ultra-long delivery purpose. The prodrug was synthesized by esterification of hydroxyl group with carboxyl group of fatty acid (lauric or myristic acid). The prodrugs were characterized by differential scanning calorimetry, X-ray powder diffraction, nuclear magnetic resonance, Fourier transformed infrared, near infrared-chemical imaging, pH-solubility, partition coefficient, and stability (solid and liquid). Stability studies were performed by exposing the powder drugs to 40°C/75% RH for three months and buffer solutions at room temperature for 72 h. The prodrugs and drug were formulated into in-situ implant using biodegradable polymer. Thermal, spectral, and diffractometric data indicated formation of new chemical and solid forms. Formation of prodrugs resulted in lowering of melting point of DTG from 191.1°C to 163.7 and 140.7°C for DTG-Laurate and DTG-Myristate prodrugs, respectively. A decrease in solubility of 18.2-115.9 and 124.5-1594.9 folds was observed for DTG-Laurate and DTG-Myristate, respectively compared to DTG. Similarly, the prodrugs were highly lipophilic compared to DTG. Solid-state and pH-stability profiles of DTG and prodrugs were comparable. Implant formulation released 60.1% in 77 days compared to 95.6% in 35 days in the case of DTG-Myristate and DTG, respectively. In summary, combining prodrug and drug delivery approaches can be utilized for delivering drug for ultra-long period. [ABSTRACT FROM AUTHOR]

Prussian blue (PB) is the active pharmaceutical ingredient (API) of Radiogardase, the first approved medical countermeasure for the treatment of radiocesium poisoning in the event of a major radiological incident such as a “dirty bomb” or nuclear attack. The purpose of this study is to assess the long-term stability of Prussian blue drug products (DPs) and APIs under laboratory storage condition by monitoring the loss in water content and the in vitro cesium binding. The water content was measured by thermal gravimetric analysis (TGA). The in-vitro cesium binding study was conducted using a surrogate model to mimic gastric residence and intestinal transport. Free cesium was analyzed using a validated flame atomic emission spectroscopy (AES) method. The binding equilibrium was reached at 24 h. The Langmuir isotherm was plotted to calculate the maximum binding capacity (MBC). Comparison of the same PB samples with 2003 data samples, the water content of both APIs and DPs decreased on an average by approximately 12–24%. Consequently, the MBC of cesium was decreased from 358 mg/g in 2003 to 265 mg/g @ pH 7.5, a decrease of approximately 26%. The binding of cesium is also pH dependent with lowest binding at pH 1.0 and maximum binding at pH 7.5. At pH 7.5, the amount of cesium bound decreased by an average value of 7.9% for APIs and 8.9% for DPs (for 600 ppm initial cesium concentration). These findings of water loss, pH dependence and decrease in cesium binding are consistent with our previously published data in 2003. Over last 10 years the stored DPs and APIs of PB have lost about 20% of water which has a negative impact on the PB cesium binding, however PB still meets the FDA specification of >150 mg/g at equilibrium. The study is the first quantitative assessment of the long-term stability of PB and directs that proper long-term and short-term storage of PB is required to ensure that it is safe and efficacious at the time of an emergency situation. [ABSTRACT FROM AUTHOR]

Abstract: The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable. [Copyright &y& Elsevier]

The objective of the study was to evaluate the stability of warfarin products during use by patients or caregivers. For evaluation, three commercial products manufactured by different processes were selected and placed at 30°C/75%RH to simulate in use condition. Samples were withdrawn up to 12 weeks and analyzed for the physicochemical changes. Scanning electron microscopy demonstrated increasing holes and craters in the tablets over the timeframe. Near-infrared chemical imaging and powder X-ray powder diffraction corroborated the change arising from conversion of crystalline to amorphous forms of the drug. Hardness and disintegration time of the tablets were found to increase progressively. With increasing time, moisture contents of the products were found to increase and consequent decrease in isopropyl alcohol content of the product. Dissolution of the tablets in media at pH 4.5 demonstrated discrimination between crystalline and amorphous drug products. Overall, percent drug dissolved in each product at 30 min was found to decrease with increasing exposure time. Dissolution of drug decreased from 54% to 38% and 82% to 54% for the two products while the third product maintained consistently high level of dissolution. These results suggest that the drug product quality attributes can change during use. [ABSTRACT FROM AUTHOR]

Drug shortages and recalls are often caused due to particulate growth in parenteral products and can have serious clinical implications. Root cause analysis of such recalls and shortages may arise due to insufficient understanding of process, formulations issues and environmental effects than often reported filtration and inadequate personnel training. Therefore, the goal of this study was to use a model peptide hormone, secretin that is currently under drug shortage, and investigate the effect of excipients on the lyophilized secretin formulation and evaluate the effect of storage and excursion temperatures. Lyophilized formulation was assayed for secretin by reverse phase HPLC. Solid state characteristics of lyophilized formulation were determined by X-ray powder diffraction (XRPD), thermal and spectroscopic methods. Dynamic light scattering (DLS) was used to detect particulates in the formulation after reconstitution. To assess the environmental impact, the lyophilized samples were stored at −20 °C, 4 °C, 25 °C and 25 °C/60%RH and analyzed at time 0, 1, 4, and 8 weeks. HPLC analyses exhibited a decrease in secretin concentration by 8 week (20–27% fold decrease). Visual observation and DLS showed particulates and increased reconstitution time ( e.g ., at 25 °C/60%RH, particle size of ∼390 nm at day 0 to >2 μm as early as week 1; reconstitution time of ∼20 s at day 0 to ∼67 s at week 8). XRPD, thermal and spectroscopic methods demonstrated polymorphic transitions of mannitol and increased crystallinity in the lyophilized formulations with time. These studies potentially address the effect of product excursions outside the proposed label storage conditions which is −20 °C for secretin formulation and this is the first time it has been investigated. These observations indicate that both environmental factor and excipient may have an impact on the stability of secretin formulation and appearance of particles in the product. [ABSTRACT FROM AUTHOR]

Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5 °C, 15 °C, 25 °C, 25 °C/60%RH, and 40 °C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60–90 °C demonstrating glass transition, 110–160 °C showing recrystallization exotherm,170–220 °C exhibiting endotherm of potential polymorph, and 250 °C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2 θ 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40 °C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues. [ABSTRACT FROM AUTHOR]

The Department of Defense ( Do D)-United States Food and Drug Administration ( FDA) shelf-life extension program ( SLEP) was established in 1986 through an intra-agency agreement between the Do D and the FDA to extend the shelf life of product nearing expiry. During the early stages of development, special attention was paid to program operation, labeling requirements, and the cost benefits associated with this program. In addition to the substantial cost benefits, the program also provides the FDA's Center for Drug Evaluation and Research with significant scientific understanding and pharmaceutical resource. As a result of this unique resource, numerous regulatory research opportunities to improve public health present themselves from this distinctive scientific database, which includes examples of products shelf life, their long-term stability issues, and various physical and chemical tests to identify such failures. The database also serves as a scientific resource for mechanistic understanding and identification of test failures leading to the development of new formulations or more robust packaging. It has been recognized that SLEP is very important in maintaining both national security and public welfare by confirming that the stockpiled pharmaceutical products meet quality standards after the 'expiration date' assigned by the sponsor. SLEP research is an example of regulatory science that is needed to best ensure product performance past the original shelf life. The objective of this article is to provide a brief history and background and most importantly the public health benefits of the SLEP. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1331-1336, 2014 [ABSTRACT FROM AUTHOR]

Abstract: The stability of metoprolol tartrate tablets packaged in original high density polyethylene containers and repackaged in USP Class A unit-dose blister packs was investigated. Studies were conducted at 25°C/60% relative humidity (RH) for 52 weeks and at 40°C/75% RH for 13 weeks. The potency, dissolution, water content, loss on drying and hardness of the drug products were analyzed. Results indicated no differences in the stability between the tablets in both packages stored under 25°C/60% RH. No difference in potency was found in both packages under either condition. However, a significant weight increase due to moisture uptake was observed for the repackaged tablets stored under 40°C/75% RH. The weight increase was accompanied by a decrease in tablet hardness (6.5–0kp) and a increase in dissolution rate (51–92%) in 5min. Near-infrared (NIR) chemical imaging also monitored moisture uptake of the tablet non-invasively through the package. The observed changes in product stability may adversely affect the products bioavailability profile, even though the potency of the active drug remained within USP specification range of 90–110%. Study results suggest product quality can be negatively impacted even when using USP Class A repackaging materials. [Copyright &y& Elsevier]

A high performance gel permeation chromatography (HP-GPC) method was developed, validated and used to determine the molecular weight (MW) of sodium ferric gluconate following various stress conditions. The intra-day accuracy (90–103%), intra-day precision (1.5–2.7%), inter-day accuracy (91–105%), inter-day precision (1.3–3.2%) were within acceptable range stated in FDA guidance. The MW of sodium ferric gluconate remained unchanged after: (1) autoclaving (121°C), (2) moderate thermal stress (30 days at 50°C or 7 days at 70 and 90°C), (3) excipient dilution, (4) basic buffer dilution (pH of 8 and 9), (5) ultracentrifugation, (6) dialysis, and (7) electrolyte dilution. However sodium ferric gluconate showed signs of instability at higher temperatures (>90°C) after 30 days and at pH of 10–11. Sodium ferric gluconate was found to be a lypophilic colloidal solution with an average particle size of 10 nm and a zeta potential of -13 mV. The colloid osmotic pressure was 3.5 mmHg and remained unchanged after moderate thermal stress. Additionally, in-house drug products with similar MW to sodium ferric gluconate were produced by three different synthetic procedures, suggesting that this colloidal iron drug product might be thermodynamically stable. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:142–153, 2010 [ABSTRACT FROM AUTHOR]

Purpose. The stability of a gabapentin 300-mg capsule product in the original bulk containers and repackaged in unit dose blister strips was studied. Methods. Both products were stored for one year under long-term storage conditions (25 °C and 60% relative humidity [RH]) and for three months under accelerated storage conditions (40 °C and 75% RH) and tested for weight change, potency, and dissolution using validated analytical method. Results. The capsules in the original containers showed no change in weight during the study period. However, the repackaged drug product stored under long-term storage conditions and under accelerated storage conditions showed significant weight increases (p < 0.001) during the study period. No significant differences in potency between the original and repackaged drug products were detected. Potency exceeded 97% for the products stored under the long-term storage conditions and exceeded 95% for the products stored under the accelerated storage conditions. At 13 weeks, samples from the original container and the blister strips stored under the accelerated storage conditions showed quantitative levels of the lactam degradation product; however, these levels were within acceptable limits. No other difference was observed between the original and the repackaged drug products, and both products remained stable throughout the study period. Conclusion. Gabapentin 300-mg capsules in the original containers and repackaged in blister strips were stable up to one year under long-term storage conditions and up to three months under accelerated storage conditions. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to determine the stability differences between split and intact gabapentin tablets. Gabapentin tablets from three different manufacturers (G1, G2 and G3) were tested for a period of 9 weeks under long-term (25°C/60% RH) and intermediate stability (30°C/60% RH) storage conditions after storage in closed amber pharmacy dispensing containers. Samples were analyzed for dissolution and potency using validated HPLC methods. Potency test also included the quantitation of gabapentin''s main degradation product. Tablets from all manufacturers and at all time points had potency >90%. At 9 weeks, a statistically significant decrease (p <0.02) in gabapentin potency was observed for the whole and split G2 and G3 tablets under the intermediate storage conditions. At the end of 9 weeks, all samples also showed slightly higher levels of degradation product which was statistically significant (p <0.01) for samples stored under intermediate stability storage conditions and exceeded the proposed USP (PF, 2006) limit for the G3 split and intact tablets. No difference was observed between the potency and dissolution of the intact and the split tablets from the same manufacturer and the three products tested remained stable throughout the study period. The results suggest that splitting of gabapentin tablets did not affect the stability of these particular drug products tested as part of this study when stored under normal storage conditions for a period of up to 9 weeks. However, the results should not be extrapolated to other gabapentin drug products and to other tablet dosage forms. [Copyright &y& Elsevier]

[Display omitted] • Palmitic acid conjugated prodrug of dolutegravir for ultra-long delivery of the drug. • The prodrug increased lipophilic character as indicated by a decrease in solubility and an increase in partition coefficient. • The prodrug quickly converted to dolutegravir in the human plasma. • The prodrug maintained IC 90 concentration of dolutegravir for 600 days. • The prodrug sustained the in vitro drug release from the microparticle for six months. The focus of present work was to characterize ultra-long acting prodrug of dolutegravir (DTG) and develop biodegradable microparticle formulation. Palmitic acid (PA) conjugated prodrug of DTG was prepared by esterification of hydroxyl group of DTG with the carboxyl group of PA. Physicochemical properties of the prodrug was characterize by MS, NMR, FTIR, SEM, DSC, NIR-CI, pH-solubility, and solid and liquid pH-stability. Comparative solid and liquid stability was performed by storing powder DTG and DTG-Palmitate at 40 °C/75% RH for three months and liquid solution pH 2–8 at room temperature for 24 h, respectively. Pharmacokinetic evaluation was performed in white albino New Zealand rabbits by subcutaneous injection (30 mg/Kg). Poly(lactide-co-glycolide) microparticle formulation was prepared by emulsification-evaporation method and characterized for particle size distribution, shape, drug loading and in-vitro release. MS, NMR, FTIR, SEM, DSC, NIR-CI indicated formation of prodrug. Melting point of the prodrug was lower than DTG but higher than PA. Shape of DTG crystals was irregular while DTG-Palmitate crystals was fine-needle. Solid and liquid stability profiles of the prodrug were similar to DTG. Plasma half-life, area under the curve, and mean-residence time of DTG-Palmitate were 8.8, 2.3 and 14.7 folds of DTG. D 90 of DTG and DTG-Palmitate microparticles was 107.1 ± 2.7 and 94.3 ± 3.4 µm, respectively. The in-vitro drug release was almost complete in three weeks from DTG microparticles while it was <85% in six months from DTG-Palmitate microparticles. In conclusion, physicochemical and pharmacokinetic properties and biodegradable microparticles of the prodrug suggested that the prodrug has potential of sustaining DTG release for ultra-long period compared to DTG. [ABSTRACT FROM AUTHOR]

Rifaximin (RFX) exhibit polymorphism and commercial formulation contains the α form. The polymorphic transformation of the RFX in the drug product have significant effect on the clinical outcome. The focus of present work was to understand effect of formulation component and manufacturing method, and exposure to stability condition on polymorphic stability and dissolution of RFX tablets. The RFX tablets containing 2.5, 5 and 10% glyceryl palmitostearate (GPS) were manufactured by direct-compression and wet-granulation followed by compression. Ethanol was used as a granulating solvent. The tablets were packed in pharmacy vials and exposed to 40 °C/75% RH for four weeks. The tablets were characterized for polymorphic form by X-ray powder diffraction (XRPD) and Fourier infrared spectroscopy (FTIR), assay and dissolution. Before exposure to stability condition, dissolution ranged from 78.0 ± 2.3 to 81.9 ± 3.5%, and 72.7 ± 2.0 and 75.9 ± 5.8% in directly compressed and ethanol-granulated formulations, respectively. GPS amount of 10% caused a decrease in dissolution albeit insignificant (p > 0.05). The polymorphic forms of RFX were α and γ in directly compressed and ethanol-granulated formulations, respectively. There was a decrease in dissolution rate and extent after exposure to 40 °C/75% RH in directly compressed formulations. On the other hand, only dissolution rate was affected in ethanol-granulated formulations. The dissolution ranged from 52.8 ± 2.0 to 70.0 ± 3.0% in directly compressed formulations after four weeks exposure to 40 °C/75% RH exposure. A decrease in dissolution was linked to polymorphic transformation of the drug and GPS in the formulations after exposure to stability condition. XRPD and FTIR data indicated α to β transformation in directly compressed formulations while no polymorphic change was observed in ethanol-granulated formulations. In conclusion, this study clearly showed effect of formulation and manufacturing variables, and stability exposure on the polymorphic stability and dissolution of RFX, which may have clinical ramification. [ABSTRACT FROM AUTHOR]