Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Development of ezetimibe eutectic with improved biopharmaceutical and mechanical properties to design an optimized oral solid dosage formulation.

Eutectics are multicomponent systems which are an alternative to the conventional techniques for modulating the biopharmaceutical properties of a pharmaceutical. Ezetimibe (ETZ) is a hypocholesterolemic agent with limited dissolution, poor water solubility, and subsequently demonstrates low oral bioavailability. Additionally, ETZ exhibits poor mechanical properties, leading to difficulties in developing dosage forms through direct compression. The present work highlights the applicability of eutectics in the simultaneous improvement of physicochemical along with mechanical properties of ETZ. A pharmaceutical eutectic of ETZ with succinimide (SUC) was prepared by mechanochemical grinding and thoroughly characterized using thermoanalytical, X-ray diffraction, and spectroscopic methods. Intrinsic dissolution rate and pharmacokinetic analysis were also performed for ezetimibe-succinimide (ETZ-SUC) eutectic in contrast to pure ETZ. The eutectic demonstrated ∼2-fold increase in the solubility and dissolution rate. In pharmacokinetic studies, the area under the curve (AUC) for ETZ-SUC eutectic (28.03 ± 2.22 ng*h/mL) was found to be higher than ETZ (8.98 ± 0.36 ng*h/mL), indicating improved oral bioavailability for eutectics. Also, it was observed that enhanced material functionality aids in designing directly compressed tablets, where the eutectic formulation showed an improved dissolution profile over the ETZ formulation. The study demonstrates that eutectic conglomerates could be utilized to develop ideal oral solid dosage formulations.

Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation.

Emerging evidence suggests that intestinal permeability can be potentially enhanced through cocrystallization. However, a mechanism for this effect remains to be established. In this study, we first demonstrate the enhancement in intestinal permeability, evaluated by the Caco-2 cell permeability assay, of acetazolamide (ACZ) in the presence of a conformer, p-aminobenzoic acid (PABA), delivered in the form of a 1:1 cocrystal. The binding strength of ACZ and PABA with the Pgp efflux transporter, either alone or as a mixture, was calculated using molecular dynamics simulation. Results show that PABA weakens the binding of ACZ with Pgp, which leads to a lower efflux ratio and elevated permeability of ACZ. This work provides molecular-level insights into a potentially effective strategy to improve the intestinal permeability of drugs. If the same cocrystal also exhibits higher solubility, oral bioavailability of BCS IV drugs can likely be improved by forming a cocrystal with a Pgp inhibitor.

Development of direct compression Acetazolamide tablet with improved bioavailability in healthy human volunteers enabled by cocrystallization with p-Aminobenzoic acid.

Pharmaceutical cocrystallization has been widely used to improve physicochemical properties of APIs. However, developing cocrystal formulation with proven clinical success remains scarce. Successful translation of a cocrystal to suitable dosage forms requires simultaneously improvement of several deficient physicochemical properties over the parent API, without deteriorating other properties critical for successful product development. In the present work, we report the successful development of a direct compression tablet product of acetazolamide (ACZ), using a 1:1 cocrystal of acetazolamide with p-aminobenzoic acid (ACZ-PABA). The ACZ-PABA tablet exhibits superior biopharmaceutical performance against the commercial tablet, DIAMOX® (250 mg), in healthy human volunteers, leading to more than 50 % reduction in the required dose.

Cocrystallization: Cutting Edge Tool for Physicochemical Modulation of Active Pharmaceutical Ingredients.

Cocrystallization is a widely accepted and clinically relevant technique that has prospered very well over the past decades to potentially modify the physicochemical properties of existing active pharmaceutic ingredients (APIs) without compromising their therapeutic benefits. Over time, it has become an integral part of the pre-formulation stage of drug development because of its ability to yield cocrystals with improved properties in a way that other traditional methods cannot easily achieve. Cocrystals are solid crystalline materials composed of two or more than two molecules which are non-covalently bonded in the same crystal lattice. Due to the continuous efforts of pharmaceutical scientists and crystal engineers, today cocrystals have emerged as a cutting edge tool to modulate poor physicochemical properties of APIs such as solubility, permeability, bioavailability, improving poor mechanical properties and taste masking. The success of cocrystals can be traced back by looking at the number of products that are getting regulatory approval. At present, many cocrystals have obtained regulatory approval and they successfully made into the market place followed by a fair number of cocrystals that are currently in the clinical phases. Considering all these facts about cocrystals, the formulation scientists have been inspired to undertake more relevant research to extract out maximum benefits. Here in this review cocrystallization technique will be discussed in detail with respect to its background, different synthesis approaches, synthesis mechanism, application and improvements in drug delivery systems and its regulatory perspective.

Development of a Thermoresponsive Polymeric Composite Film Using Cross-Linked ß-Cyclodextrin Embedded with Carbon Quantum Dots as a Transdermal Drug Carrier.

Polymeric nanocomposite films are used as promising transdermal drug carriers because of the improved patient compliance, easy application on skin, and noninvasiveness. A thermoresponsive polymeric composite film has been developed here through the deposition of carbon quantum dots (CQDs) on functionalized ß-cyclodextrin (ß-CD). The composite has been developed by grafting of poly(N-vinyl caprolactam) on ß-CD, followed by cross-linking of diethylene glycol dimethacrylate and subsequent deposition of CQDs. CQDs have been prepared from waste pomegranate peels via a hydrothermal method. To enlighten the thermoresponsive nature of the composite film, lower critical solution temperature, as well as temperature-dependent swelling behavior, has been studied. The composite demonstrates excellent rheological features. The developed polymeric composite film is nontoxic toward NIH 3T3 fibroblast cell lines. On the deposition of CQDs on the copolymer, the penetration power and fluorescent property have been improved, which help to track the cells in vitro. This film is worthy to be applied to the skin. It can efficiently load lidocaine hydrochloride monohydrate (LHM). In vitro and ex vivo skin permeation profiles reveal the sustained release behavior of loaded LHM at average skin temperature and pH.

Enhanced Solubility of Telmisartan Phthalic Acid Cocrystals within the pH Range of a Systemic Absorption Site.

Telmisartan (TLM), a nonpeptide angiotensin II antagonist, is widely prescribed for treating arterial hypertension and marketed by the innovator with the trade name of Micardis and Micardis plus. Telmisartan exhibits low aqueous solubility in the pH range of 3-7, which is the physiological pH. For addressing the issue of poor solubility of TLM, its commercial form makes use of inorganic alkalinizers. The present work illustrates the attempt to improve the solubility of telmisartan via a crystal engineering approach. A novel solid form of telmisartan with phthalic acid was obtained through the solution crystallization method (TPS) and the reaction crystallization method (TPR). Both the forms (TPS and TPR) were thoroughly characterized by powder diffraction X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and 1H NMR and were identified to be two different crystalline forms. Solubility studies of TPS and TPR were conducted at varying pH of phosphate buffer, and they exhibited 11-fold and 22-fold increased solubility, respectively, when compared to that of the pure drug at pH 5, which is within the pH of small intestine at which telmisartan is best absorbed orally from the systemic circulation.

Synthesis and characterization of a non-cytotoxic and biocompatible acrylamide grafted pullulan - Application in pH responsive controlled drug delivery.

The aim of present study was to develop a pH responsive rate controlling polymer by acrylamide grafting onto pullulan. Grafting was performed using free radical induced microwave assisted irradiation technique using ceric ammonium nitrate as free radical inducer. Acrylamide grafted pullulan (Aam-g-pull) was characterized by Fourier transform infrared spectroscopy, solid state 13C nuclear magnetic resonance and field emission scanning electron microscopy. In vitro enzymatic degradation of Aam-g-pull showed degradation of 22.45% after 8 h with degradation rate constant (k) of 0.019 min-1. In vitro cytotoxicity test did not show cell viability below 80% on HepG2 cell line. Pirfenidone tablets were prepared by utilizing wet granulation method using Aam-g-pull as the only rate controlling polymer. The tablets were characterized in terms of in-process quality control parameters like weight variation, hardness, assay, and in vitro dissolution study. The dissolution study showed that the cumulative drug release in phosphate buffer pH 6.8 (rel3 h = 44.12 ±â€¯0.56%) got a significant jump as compared to the release in 0.1 N hydrochloric acid (rel2 h = 26.78 ±â€¯0.23%), confirming the material to be pH responsive. Aam-g-pull can be used as pH responsive rate controlling polymer.

In vitro and in vivo evaluation of pirfenidone loaded acrylamide grafted pullulan-poly(vinyl alcohol) interpenetrating polymer networks.

The aim of present study was to develop controlled release formulation of pirfenidone using acrylamide grafted pullulan. Interpenetrating polymer network (IPN) microspheres were prepared using acrylamide grafted pullulan and PVA utilizing glutaraldehyde assisted water-in-oil emulsion crosslinking method. IPN microspheres were characterized by FTIR, solid state 13C NMR and XRD spectroscopy. In vitro enzymatic degradation study showed 34.30% degradation after 24 h with degradation rate constant of 0.0088 min-1. In vitro biocompatibility test showed no changes in cellular morphology and cell adherence to microspheres, indicating its biocompatible nature. The release exponent value of all formulations was less than 0.45, indicating the release mechanism to be Fickian diffusion. Finally, in vivo pharmacokinetic study showed longer Tmax (1.16 h) and greater AUC value (10037.76 ng h/mL,) as compared to Pirfenex® (Tmax = 0.5 h; AUC = 4310.45 ng h/mL,). The results indicated that the prepared formulation could successfully control the drug release for prolonged time period.

Therapeutically Effective Controlled Release Formulation of Pirfenidone from Nontoxic Biocompatible Carboxymethyl Pullulan-Poly(vinyl alcohol) Interpenetrating Polymer Networks.

The present study was conducted to develop therapeutically effective controlled release formulation of pirfenidone (PFD) and explore the possibility to reduce the total administered dose and dosing regimen. For this purpose, pH-sensitive biomaterial was prepared by inducing carboxymethyl group on pullulan by Williamson ether synthesis reaction, and further, interpenetrating polymeric network microspheres were prepared by glutaraldehyde-assisted water-in-oil (w/o) emulsion cross-linking method, which showed higher swelling ratio in acidic and basic pH. The formation of microspheres was confirmed by different spectral characterization techniques, and thermal kinetic study indicated the formation of thermally stable microspheres. Cell viability and biocompatibility studies on hepatocellular carcinoma (HepG2) cell showed the polymeric matrix to be biocompatible. In vitro dissolution of optimized formulation (F5) showed releases of 54.09 and 76.37% in 0.1 N HCl after 2 h and phosphate buffer (pH 6.8) up to 8 h, respectively. In vivo performances of prepared microsphere and marketed product of PFD were compared in rabbit. T max (time taken to reach peak plasma concentration) was found to be achieved at 0.83 h, compared to 0.5 h for Pirfenex with no significant difference complementing the immediate action, while area under curve was significantly greater for optimized formulation (9768 ± 1300 ng h/mL) compared to Pirfenex (4311 ± 110 ng h/mL), complementing the sustained action. In vivo pharmacokinetic study suggested that the prepared microsphere could be a potential candidate for therapeutically effective controlled delivery of PFD used in dyspnea and cough management due to idiopathic pulmonary fibrosis.