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.

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.

Prolonged response to Tyrosine Kinase Inhibitors followed by Immunotherapy in metastatic hepatocellular carcinoma: A rare case report.

The overall prognosis of hepatocellular carcinoma (HCC) is dismal and 5-year survival rate is 14.8%. We report a case of HCC coinfected with hepatitis C virus (HCV) and tumor thrombosis in the portal vein that was initially started on sorafenib followed by lenvatinib and nivolumab. On radiological imaging, there was a good partial response (PR) after starting nivolumab. A female 56 years of age presented with HCC coinfection with HCV, tumor thrombosis growing to the right portal vein. She received 6 months of sorafenib starting from April 2019 and was then switched to lenvatinib due to progressive disease. She continued lenvatinib for 11 months following which she developed new metastatic lesions where she was started on nivolumab. After 4 months of nivolumab, her alpha-fetoprotein decreased and there was a radiological PR. She is currently on nivolumab, with a total duration of response of 24 months on sorafenib followed by lenvatinib and lastly on nivolumab. Hence, tyrosine kinase inhibitors and immunotherapy can be effective lines treatment for advanced HCC and can give durable response duration, and probable radiological PR can be achieved with Nivolumab.

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.

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.

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.

Crystal structure of (2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ato-κ(3) O (4),N (5),O (6))aqua-(1,10-phenanthroline-κ(2) N,N')zinc trihydrate.

In the title compound, [Zn(C8H5N5O3)(C12H8N2)(H2O)]·3H2O, a tridentate 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate ligand, a bidentate ancillary 1,10-phenanthroline (phen) ligand and a water mol-ecule complete a distorted octa-hedral coordination geometry around the Zn(II) atom. The pterin ligand forms two chelate rings. The phen and pterin ring systems are nearly perpendicular [dihedral angle = 85.16 (5)°]. Classical N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds and weak C-H⋯O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a three-dimensional network. π-π stacking contacts are observed as well, with centroid-to-centroid distances of 3.5679 (14), 3.7004 (14), 3.6641 (15), 3.6974 (13) and 3.3412 (12) Å.

Crystal structure of (2-amino-7-methyl-4-oxido-pteridine-6-carboxyl-ato-κ(3) O (4),N (5),O (6))aqua-(1,10-phenanthroline-κ(2) N,N')copper(II) trihydrate.

In the title compound, [Cu(C8H5N5O3)(C12H8N2)(H2O)]·3H2O, the Cu(II) cation is O,N,O'-chelated by the 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate anion and N,N'-chelated by the 1,10-phenanthroline (phen) ligand. A water mol-ecule further coordinates to the Cu(II) cation to complete the elongated distorted octa-hedral coordination geometry. In the mol-ecule, the pteridine ring system is essentially planar [maximum deviation = 0.055 (4) Å], and its mean plane is nearly perpendicular to the phen ring system [dihedral angle = 85.97 (3)°]. In the crystal, N-H⋯O, O-H⋯N and O-H⋯·O hydrogen bonds, as well as weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions, link the complex mol-ecules and lattice water mol-ecules into a three-dimensional supra-molecular architecture. Extensive π-π stacking between nearly parallel aromatic rings of adjacent mol-ecules are also observed, the centroid-to-centroid distances being 3.352 (2), 3.546 (3), 3.706 (3) and 3.744 (3) Å.

(2-Amino-7-methyl-4-oxidopteridine-6-carboxyl-ato-κ(3) O (4),N (5),O (6))(ethane-1,2-diamine-κ(2) N,N')(1H-imidazole-κN (3))nickel(II) dihydrate.

In the title complex, [Ni(C8H5N5O3)(C2H8N2)(C3N2H4)]·2H2O, a tridentate 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate (pterin) ligand, a bidentate ancillary ethane-1,2-diamine (en) ligand and a monodentate 1H-imidazole (im) ligand complete a distorted octa-hedral geometry around the Ni(II) atom. The pterin ligand forms two chelate rings. Both the en and im ligands are arranged nearly orthogonally relative to the pterin ligand [dihedral angles between the mean planes of the en and pterin ligands and of the im and pterin ligands are 84.62 (9) and 85.14 (9)°, respectively]. N-H⋯N, N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a three-dimensional network.

(2-Amino-7-methyl-4-oxido-pteridine-6-carboxyl-ato-κ(3) O (4),N (5),O (6))aqua(1,10-phen-an-thro-line-κ(2) N,N')cobalt(II) trihydrate.

In the title compound, [Co(C8H5N5O3)(C12H8N2)(H2O)]·3H2O, a tridentate 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate ligand, a bidentate ancillary 1,10-phenanthroline (phen) ligand and a water mol-ecule complete a distorted octa-hedral geometry around the Co(II) atom. The pterin ligand forms two chelate rings. The phen and pterin ring systems are nearly perpendicular [dihedral angle = 85.15 (8)°]. N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a layer parallel to (001). π-π stacking contacts (involving phen-phen and pteridine-pteridine) are also observed [centroid-centroid distances = 3.670 (2), 3.547 (2), 3.698 (2) and 3.349 (2) Å].

(2-Amino-7-methyl-4-oxidopteridine-6-carboxyl-ato-κ(3)O(4),N(5),O(6))aqua-(ethane-1,2-diamine-κ(2)N,N')nickel(II) dihydrate.

The Ni(II) atom in the title complex, [Ni(C(8)H(5)N(5)O(3))(C(2)H(8)N(2))(H(2)O)]·2H(2)O, is six-coordinated in a distorted octa-hedral geometry by a tridentate 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate (pterin) ligand, a bidentate ancillary ethane-1,2-diamine (en) ligand and a water mol-ecule. The pterin ligand forms two chelate rings. The en and pterin ligands are arranged nearly orthogonally [dihedral angle between the mean plane of the en mol-ecule and the pterin ring = 77.1 (1)°]. N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a three-dimensional network. π-π inter-actions are observed between the pyrazine and pyrimidine rings [centroid-centroid distance = 3.437 (2) Å].