HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus­Based In Vivo Prediction in Humans: Part II.

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Potentially active aspirin derivative to release nitric oxide: In-vitro, in-vivo and in-silico approaches.

The series of newer salicylate derivatives incorporating nitroxy functionality were synthesized and evaluated for their potential effect in gastrointestinal (GI) related toxicity produced by aspirin. The synthesized compounds (5a-j) were subjected to %NO (nitric oxide) release study, in-vitro anti-inflammatory potential, % inhibition of carrageenan-induced paw edema and the obtained results were validated by in-silico studies including molecular docking, MD simulations and in-silico ADME (absorption, distribution, metabolism, and elimination) calculations. Compounds 5a (20.86 %) and 5g (18.20 %) displayed the highest percentage of NO release in all the tested compounds. Similarly, 5a and 5h were found to have (77.11 % and 79.53 %) &(78.56 % and 66.10 %) inhibition in carrageenan induced paw edema in animal mode which were relatively higher than ibuprofen (standard used). The obtained results were validated by molecular docking and MD simulations studies. The molecular docking study of 5a and 5h revealed that docking scores were also obtained in very close proximity of -8.35, -9.67 and -8.48 for ibuprofen, 5g and 5h respectively. In MD simulations studies, the calculated lower RMSD (root mean square deviation) values 2.8 Å and 5.6 Å for 5g and 5h, respectively indicated the stability of ligand-protein complexes. Similarly lower RSMF (root mean square fluctuation) values indicated the molecules remained in the active pocket throughout the entire MD simulations run. Further, in-silico ADME calculations were determined and all compounds obey the Lipinski's rule of five and it was predicted that these molecules would be orally active without any serious toxic effect.

A correlation between oxidative stress and diabetic retinopathy: An updated review.

Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.

Identification of Potential Antitubulin Agents with Anticancer Assets from a Series of Imidazo[1,2-a]quinoxaline Derivatives: In Silico and In Vitro Approaches.

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33-6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles.

HSPiP and QbD Program-Based Analytical Method Development and Validation to Quantify Ketoconazole in Dermatokinetic Study.

Ketoconazole (KTZ) is the most potential azole anti-mycotic drug. The quantification of KTZ from various layers of the skin after topical application of lipidic nanocarriers is critical. We addressed a sensitive, specific, simple, rapid, reproducible, and economic analytical method to quantify KTZ from the treated skin homogenate using the Hansen solubility parameter (HSP, HSPiP software)-based modeling and experimental design. The software provided various HSP values for KTZ and solvents to compose the mobile phase. The Taguchi model identified the significant sets of factors to develop a robust bioanalytical method with reduced variability. In the optimization, acetonitrile (ACN) concentration (X1 as A) and the pH of mobile phase (X2 as B) were two factors against two responses (Y1: peak area and Y2: retention time). The HPLC (high-performance liquid chromatography) method validation was carried out based on US-FDA guidelines for the developed KTZ formulations (suspension, solid nanoparticles, and commercial product) extracted from the treated rat skin. The experimental solubility of KTZ was found to be maximum in the two solvents (ACN and ethyl acetate), based on HSP values. Surface response methodology (SRM) identified remarkable impact of ACN concentration and the mobile phase pH on the peak area and retention time. Analytical limits (0.17 and 0.50 µg/mL) were established for KTZ-SLNs (extracted from the skin). The method was implemented with high reproducibility, accuracy, and selectivity to quantify KTZ from the treated rat skin.

Hydroethanolic Extract of Urtica dioica L. (Stinging Nettle) Leaves as Disaccharidase Inhibitor and Glucose Transport in Caco-2 Hinderer.

Herbal treatment for diabetes mellitus is widely used. The pharmacological activity is thought to be due to the phenolic compounds found in the plant leaves. The present study aims to investigate the phytochemical composition of Urtica dioica (UD) hydroethanolic extract and to screen its antidiabetic activity by disaccharidase hindering and glucose transport in Caco-2 cells. The results have shown that a total of 13 phenolic compounds in this work, viz. caffeic and coumaric acid esters (1, 2, 4-7, 10), ferulic derivative (3), and flavonoid glycosides (8, 9, 11-13), were identified using HPLC-DAD-ESI/MS2. The most abundant phenolic compounds were 8 (rutin) followed by 6 (caffeoylquinic acid III). Less predominant compounds were 4 (caffeoylquinic acid II) and 11 (kaempferol-O-rutinoside). The UD hydroethanolic extract showed 56%, 45%, and 28% (1.0 mg/mL) inhibition level for maltase, sucrase, and lactase, respectively. On the other hand, glucose transport was 1.48 times less at 1.0 mg/mL UD extract compared with the control containing no UD extract. The results confirmed that U. dioica is a potential antidiabetic herb having both anti-disaccharidase and glucose transport inhibitory properties, which explained the use of UD in traditional medicine.

Formulation of Piperine-Chitosan-Coated Liposomes: Characterization and In Vitro Cytotoxic Evaluation.

The present research work is designed to prepare and evaluate piperine liposomes and piperine-chitosan-coated liposomes for oral delivery. Piperine (PPN) is a water-insoluble bioactive compound used for different diseases. The prepared formulations were evaluated for physicochemical study, mucoadhesive study, permeation study and in vitro cytotoxic study using the MCF7 breast cancer cell line. Piperine-loaded liposomes (PLF) were prepared by the thin-film evaporation method. The selected liposomes were coated with chitosan (PLFC) by electrostatic deposition to enhance the mucoadhesive property and in vitro therapeutic efficacy. Based on the findings of the study, the prepared PPN liposomes (PLF3) and chitosan coated PPN liposomes (PLF3C1) showed a nanometric size range of 165.7 ± 7.4 to 243.4 ± 7.5, a narrow polydispersity index (>0.3) and zeta potential (-7.1 to 29.8 mV). The average encapsulation efficiency was found to be between 60 and 80% for all prepared formulations. The drug release and permeation study profile showed biphasic release behavior and enhanced PPN permeation. The in vitro antioxidant study results showed a comparable antioxidant activity with pure PPN. The anticancer study depicted that the cell viability assay of tested PLF3C2 has significantly (p < 0.001)) reduced the IC50 when compared with pure PPN. The study revealed that oral chitosan-coated liposomes are a promising delivery system for the PPN and can increase the therapeutic efficacy against the breast cancer cell line.

Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus.

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (xe) was validated using the Van 't Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy ΔsolH°, entropy ΔsolS°, and Gibbs free energy ΔsolG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10-1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10-5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on xe gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of ΔsolH° and ΔsolG°. Interestingly, ΔsolG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of ΔsolG° and ΔsolS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.

Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin.

We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2-318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and van't Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10-2) ˃ methanol (6.8 × 10-2) ˃ PEG400 (4.8 × 10-2) ˃ tween 20 (3.4 × 10-2). The drug dissolution was endothermic process and entropy driven as evident from "apparent thermodynamic analysis". The activity coefficients confirmed facilitated RIF-NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.

Formulation of Gelucire®-Based Solid Dispersions of Atorvastatin Calcium: In Vitro Dissolution and In Vivo Bioavailability Study.

Atorvastatin (ATV) is a poorly water-soluble drug that exhibits poor oral bioavailability. Therefore, present research was designed to develop ATV solid dispersions (SDs) to enhance the solubility, drug release, and oral bioavailability. Various SDs of ATV were formulated by conventional and microwave-induced melting methods using Gelucire®48/16 as a carrier. The formulated SDs were characterized for different physicochemical characterizations, drug release, and oral bioavailability studies. The results obtained from the different physicochemical characterization indicate the molecular dispersion of ATV within various SDs. The drug polymer interaction results showed no interaction between ATV and used carrier. There was marked enhancement in the solubility (1.95-9.32 folds) was observed for ATV in prepared SDs as compare to pure ATV. The drug content was found to be in the range of 96.19% ± 2.14% to 98.34% ± 1.32%. The drug release results revealed significant enhancement in ATV release from prepared SDs compared to the pure drug and the marketed tablets. The formulation F8 showed high dissolution performance (% DE30 value of 80.65 ± 3.05) among the other formulations. Optimized Gelucire®48/16-based SDs formulation suggested improved oral absorption of atorvastatin as evidenced with improved pharmacokinetic parameters (Cmax 2864.33 ± 573.86 ng/ml; AUC0-t 5594.95 ± 623.3 ng/h ml) as compared to ATV suspension (Cmax 317.82 ± 63.56 ng/ml; AUC0-t 573.94 ± 398.9 ng/h ml) and marketed tablets (Cmax 852.72 ± 42.63 ng/ml; 4837.4 ± 174.7 ng/h ml). Conclusively, solid dispersion-based oral formulation of atorvastatin could be a promising approach for enhanced drug solubilization, dissolution, and subsequently improved absorption.

Formulation and Evaluation of Supramolecular Food-Grade Piperine HP ß CD and TPGS Complex: Dissolution, Physicochemical Characterization, Molecular Docking, In Vitro Antioxidant Activity, and Antimicrobial Assessment.

The purpose of the present study was to improve the aqueous solubility, dissolution, and antioxidant activity of the water-insoluble drug piperine (PIP). The study was performed by preparing PIP binary inclusion complex (PIP BIC) and piperine ternary inclusion complex (PIP TIC) by different methods. The effect of a hydrophilic auxiliary substance (TPGS) was assessed with addition to PIP and hydroxypropyl beta cyclodextrin (HP ß CD) complex. The phase solubility study was performed to evaluate the complexation efficiency and stability constant. The aqueous solubility, dissolution, physicochemical assessment, antioxidant activity, antimicrobial activity, and molecular docking were further evaluated to check the effect of the complexation of PIP. The stability constant (Ks) value was found to be 238 and 461 M-1 for the binary and ternary inclusion complex. The dissolution study results showed a marked enhancement of release in comparison to pure drug. XRD and SEM studies revealed the presence of more agglomerated and amorphous structures of PIP, which confirmed the formation of complexes. The results of DPPH radical scavenging and antimicrobial activity showed a significant (p < 0.05) enhancement in scavenging activity for PIP TIC (microwave irradiation (MI)). The docking studies have revealed that the binding affinity of TPGS at the PIP-HP ß CD complex was -5.2 kcal/mol.

Stimulatory Effects of Soluplus® on Flufenamic Acid ß-Cyclodextrin Supramolecular Complex: Physicochemical Characterization and Pre-clinical Anti-inflammatory Assessment.

The present study demonstrates the solubility and dissolution of flufenamic acid (FLF)/ß-cyclodextrin (ß-CD)/Soluplus® supramolecular ternary inclusion complex. The binary and ternary inclusion complexes were prepared using solvent evaporation and the microwave irradiation method. The prepared inclusion complexes were evaluated for physicochemical characterization and anti-inflammatory activity using a murine paw edema mol. The phase solubility studies demonstrated 4.59-fold and 17.54-fold enhancements in FLF solubility with ß-CD alone and ß-CD:Soluplus® combination compared with pure FLF, respectively. The in vitro drug release results revealed a significant improvement (P < 0.05) in the release pattern compared with pure FLF. Maximum release was found with flufenamic acid binary and ternary complexes prepared using the microwave irradiation method, i.e., 75.23 ± 3.12% and 95.36 ± 3.23% in 60 min, respectively. The physicochemical characterization results showed complex formation and conversion of the crystalline form of FLF to an amorphous form. The SEM study revealed the presence of a more agglomerated and amorphous structure of the solid particles, which confirmed the formation of complexes. The anti-inflammatory effect of the complex was higher than pure FLF. Therefore, the FLF:ß-CD:Soluplus® inclusion complex may be a very valuable formulation with improved solubility, dissolution, and anti-inflammatory effect.

Development and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for curcumin transdermal delivery: an anti-inflammatory exposure.

The purpose of this work is to develop novel lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) as carriers for transdermal delivery of curcumin. SNEDDS containing black seed oil, medium chain mono- and diglycerides and surfactants, were prepared as curcumin delivery vehicles. Their formation spontaneity, morphology, droplet size, and drug loading were evaluated. Gel preparation containing two of the SNEDDS formulations were used in the carrageenan induced paw edema to evaluate the anti-inflammatory effect. Results showed droplet size as low as 71 nm. The highest drug loading was observed with SNEDDS-F6 of ∼45 mg/g. In in-vivo investigation, SNEDDS-F6 exhibited significant anti-inflammatory activities in terms of 80% reduction in paw edema when compared with positive control. The prepared SNEDDS with the elevated entrapment efficiency, good transdermal penetration ability could be a suitable candidate for effective transdermal curcumin skin delivery.

Evaluation of the bioavailability of hydrocortisone when prepared as solid dispersion.

This study was conducted to formulate, characterize, and investigate the bioavailability of hydrocortisone (HCT) when prepared as solid dispersions. HCT was mixed in an organic solvent with polyethylene glycol 4000 (PEG 4000) and Kolliphor® P 407. Spray drying technique was employed to form a solid dispersion formulation at a specific ratio. Physical and chemical characterization of the formed particles were achieved using differential scanning calorimetry, scanning electron microscopy, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. Furthermore, comparative in vitro and in vivo studies were conducted between the formulated particles against neat HCT. The formulated solid dispersion showed elongated particles with leaf-like structure. Formation of new chemical bonds in the formed particle was suggested due to the change in the vibrational wave numbers and the significant improvement in the bioavailability of the dispersed particles proved the importance of this technique.

In vitro dissolution and bioavailability study of furosemide nanosuspension prepared using design of experiment (DoE).

BACKGROUND: Nanotechnology can offer the advantages of increasing solubility and bioavailability of delivering drugs like Furosemide. The aim of the current study is to investigate the in vitro and in vivo performance of furosemide nanosuspensions. METHODS: Furosemide nanosuspensions were prepared by antisolvent precipitation method using full factorial experimental design. Four factors were employed namely; Stirring time, Injection rate, antisolvent: solvent ratio & stabilizer: drug ratio (at two levels = high & low). The in vitro dissolution experiments were conducted to compare the representative formulation with raw drug powder. The bioavailability of nanosuspension was, also, evaluated in mice as an animal model. RESULTS: Solid state characterization (PXRD, DSC and FESEM) did show physical changes during preparation and optimization of the furosemide nanosuspensions. Individual material attributes showed more significant impact on the average particle size of the nanocrystals compared to process parameters. Two-way interactions between material attributes and process parameters significantly affected nanosuspension particle size distribution. Dissolution rate of furosemide nanosuspemsion was significantly higher than that observed for raw furosemide powder. The in vivo pharmacokinetics parameters of nanosuspension in comparison to pure drug showed significant increase in Cmax and AUC(0-t), about 233% and 266%, respectively. The oral bioavailability of furosemide from nanosuspension was about 2.3 fold higher as compared with the bioavailability from pure drug. CONCLUSIONS: Furosemide nanosuspensions prepared using antisolvent precipitation method enhanced the dissolution rate and oral bioavailability compared to raw furosemide powder.

Investigation of the in vitro performance difference of drug-Soluplus® and drug-PEG 6000 dispersions when prepared using spray drying or lyophilization.

PURPOSE: To evaluate the physicochemical and in vitro characteristics of solid dispersions using BCS II model drugs with Soluplus® and one of its component homopolymers, PEG 6000. METHODS: Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3% and 99.5% purity, respectively, were selected as BCS II model drugs, such that an improved dissolution rate and concentration in the gastrointestinal tract should increase oral bioavailability. Soluplus® is an amorphous, tri-block, graft co-polymer with polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol (PCL:PVAc:PEG6000) in the ratio 57:30:13. PEG 6000 (BASF) is a waxy material with melting point of about 60 °C. Solid dispersions were prepared using lyophilization or spray drying techniques. Dissolution study, crystallinity content, and analysis for new chemical bond formation have been used to evaluate the dispersed materials. RESULTS: Although each polymer improved the drug dissolution rate, dissolution from Soluplus® was slower. Enhanced dissolution rates were observed with NIF solid dispersions, but the dissolution profiles were quite different due to the selected technique, polymer, and dissolution medium. For SMX, there was similarity across the dissolution profiles despite the medium, polymer, or applied technique. Each polymer was able to maintain an elevated drug concentration over the three hour duration of the dissolution profile, i.e., supersaturation was supported by the polymer. DSC thermograms revealed no melting endotherm, suggesting that the drug is amorphous or molecularly dispersed. CONCLUSION: NIF and SMX solid dispersions were successfully prepared by spray drying and lyophilization using Soluplus® or PEG 6000. Each polymer enhanced the drug dissolution rate; NIF dissolution rate was improved to a greater extent. Dispersions with PEG 6000 had a faster dissolution rate due to its hydrophilic nature. DSC analysis showed that no crystalline material exists in the dispersions.

Use of the Flory-Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus.

CONTEXT: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. OBJECTIVE: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. MATERIALS AND METHODS: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. RESULTS: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. DISCUSSION: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. CONCLUSION: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

Use of the Flory-Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus.

CONTEXT: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. OBJECTIVE: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. MATERIALS AND METHODS: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. RESULTS: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. DISCUSSION: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. CONCLUSION: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

HSPiP, Computational Modeling, and QbD-Assisted Optimized Method Validation of 5-Fluorouracil for Transdermal Products.

This study addressed the simplest and most efficient HPLC (high-performance liquid chromatography) method for the estimation of 5-fluorouracil (5-FU) from rat blood plasma by implementing the Hansen solubility parameters (HSP), computation prediction program, and QbD (quality by design) tool. The mobile phase selection was based on the HSP predictions and experimental data. The Taguchi model identified seven variables (preoptimization) to screen two factors (mobile phase ratio as A and column temperature as B) at three levels as input parameters in "CCD (central composite design)" optimization (retention time as Y1 and peak area as Y2). The stability study (freeze-thaw cycle and short- and long-term stability) was conducted in the rat plasma. Results showed that HSPiP-based HSP values and computational model-based predictions were well simulated with the experimental solubility data. Acetonitrile (ACN) was relatively suitable over methanol as evidenced by the experimental solubility value, HSP predicted parameters (δh of 5-FU - δh of ACN = 8.3-8.3 = 0 as high interactive solvent whereas δh of 5-FU - δh of methanol = 8.3-21.7 = -13.4), and instrumental conditions. CCD-based dependent variables (Y1 and Y2) exhibited the best fit of the model as evidenced by a high value of combined desirability (0.978). The most robust method was adopted at A = 96:4 and B = 40 °C to get earlier Y1 and high Y2 as evidenced by high desirability (D) = 0.978 (quadratic model with p < 0.0023). The estimated values of LLOD and LLOQ were found to be 0.11 and 0.36 µg/mL, respectively with an accuracy range of 94.4-98.7%. Thus, the adopted method was the most robust, reliable, and reproducible methodology for pharmacokinetic parameters after the transdermal application of formulations in the rat.