The solvation and dissociation of 4-benzylaniline hydrochloride in chlorobenzene

A reaction scheme is proposed to account for the liberation of 4-benzylaniline from 4-benzylaniline hydrochloride, using chlorobenzene as a solvent at a temperature of 373 K. Two operational regimes are explored: “closed” reaction conditions correspond to the retention of evolved hydrogen chloride gas within the reaction medium, whereas an “open” system permits gaseous hydrogen chloride to be released from the reaction medium. The solution phase chemistry is analyzed by 1H NMR spectroscopy. Complete liberation of solvated 4-benzylaniline from solid 4-benzylaniline hydrochloride is possible under “open” conditions, with the entropically favored conversion of solvated hydrogen chloride to the gaseous phase thought to be the thermodynamic driver that effectively controls a series of interconnecting equilibria. A kinetic model is proposed to account for the observations of the open system

Clofazimine acid-base solubilization: influence of small organic acids’ concentration

Methods for drug solubilization have become important part of modern drug discovery and development due to increasing number of extremely insoluble drugs and drug candidates. One of such methods is acid-base supersolubilization (ABS) [1]. Clofazimine (CFZ) is weakly basic antibiotic and anti-inflammatory drug, most notably used in the treatment of leprosy and tuberculosis, with recently proven inhibitory activity against several coronaviruses [2]. We have recently unraveled its aqueous pKa value and its unique cosolvent dependence [3]. The aim of the present study was to investigate CFZ solubilization using the ABS approach. Eight small organic acids were tested for the ABS effect (glutaric, malic, tartaric, citric, malonic, maleic, succinic, adipic) but only glutaric (GA), malic (MA), and tartaric (TA) acids showed some solubilization effect. The effect of their concentration (and the solution pH value) was further tested. The solubility of CFZ was determined in GA, MA, and TA solutions in wide concentration (1.0×10-2 – 5.0 M) and pH range (~0.2 – 4.8). Equilibration time was 24 hours (6 h of stirring + 18 h of sedimentation). Phases were separated by filtration. The CFZ concentration in supernatant was determined by HPLC-UV/VIS. Results show that CFZ solubility increases as acid concentration increases: from 3.04×10-3 to 10.68 mg/mL (in GA), from 9.06×10-3 to 1.23 mg/mL (in MA) and from 4.76×10-3 to 0.32 mg/mL (in TA). The effect of CFZ solubilization is much more pronounced when the acid concentration is raised above 2 M. These results can be used as the basis for further CFZ formulation optimization. Furthermore, our ongoing research is focused on the type of interactions and other possible factors that can influence CFZ and other prectically insoluble drugs, embracing (super)solubilization as a general methodology in drug design and development

Clofazimine acid-base solubilization: influence of small organic acids’ concentration

Methods for drug solubilization have become important part of modern drug discovery and development due to increasing number of extremely insoluble drugs and drug candidates. One of such methods is acid-base supersolubilization (ABS) [1]. Clofazimine (CFZ) is weakly basic antibiotic and anti-inflammatory drug, most notably used in the treatment of leprosy and tuberculosis, with recently proven inhibitory activity against several coronaviruses [2]. We have recently unraveled its aqueous pKa value and its unique cosolvent dependence [3]. The aim of the present study was to investigate CFZ solubilization using the ABS approach. Eight small organic acids were tested for the ABS effect (glutaric, malic, tartaric, citric, malonic, maleic, succinic, adipic) but only glutaric (GA), malic (MA), and tartaric (TA) acids showed some solubilization effect. The effect of their concentration (and the solution pH value) was further tested. The solubility of CFZ was determined in GA, MA, and TA solutions in wide concentration (1.0×10-2 – 5.0 M) and pH range (~0.2 – 4.8). Equilibration time was 24 hours (6 h of stirring + 18 h of sedimentation). Phases were separated by filtration. The CFZ concentration in supernatant was determined by HPLC-UV/VIS. Results show that CFZ solubility increases as acid concentration increases: from 3.04×10-3 to 10.68 mg/mL (in GA), from 9.06×10-3 to 1.23 mg/mL (in MA) and from 4.76×10-3 to 0.32 mg/mL (in TA). The effect of CFZ solubilization is much more pronounced when the acid concentration is raised above 2 M. These results can be used as the basis for further CFZ formulation optimization. Furthermore, our ongoing research is focused on the type of interactions and other possible factors that can influence CFZ and other prectically insoluble drugs, embracing (super)solu bilization as a general methodology in drug design and development

Revealing the story of an orphan drug: clofazimine speciation and solubilization as a function of pH

Since the introduction of combinatorial chemistry and high-throughput screening in drug discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo complicated reactions in aqueous solution, such as forming precipitates or complexes with buffer species or undergoing self-aggregation (dimer, trimer, etc.)1,2 or micelle formations. Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, determined by a suitable method. In a pH-dependent measurement of a property (e.g. solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of measured values, but paradoxically, such preference can lead to inaccurate rationalization of the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, the use of calculated pKas can substantially wrench the interpretation of solution properties. Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 40 years, exhibits some of the properties of relatively recent drug molecules by being extremely water insoluble and having variable pKa values reported. We have recently combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along the hydrophobic molecular surface. With lessened exposure of the hydrophobic surface to water, the dimer would be more water soluble than the monomeric free base. In saturated solutions, the apparent solubility in alkaline pH would be elevated due to the presence of the dimer. The effect of that would be a lower pKa and reverse pKa cosolvent dependence – the behaviour we have noticed in CFZ aqueous solutions. These findings are of paramount importance for understanding of CFZ speciation and the future progress in developing its improved formulations which is the subject of our ongoing studies

Revealing the story of an orphan drug: clofazimine speciation and solubilization as a function of pH

Since the introduction of combinatorial chemistry and high-throughput screening in drug discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo complicated reactions in aqueous solution, such as forming precipitates or complexes with buffer species or undergoing self-aggregation (dimer, trimer, etc.) or micelle formations. Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, determined by a suitable method. In a pH-dependent measurement of a property (e.g. solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of measured values, but paradoxically, such preference can lead to inaccurate rationalization of the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, the use of calculated pKas can substantially wrench the interpretation of solution properties. Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 40 years, exhibits some of the properties of relatively recent drug molecules by being extremely water insoluble and having variable pKa values reported. We have recently combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along the hydrophobic molecular surface. With lessened exposure of the hydrophobic surface to water, the dimer would be more water soluble than the monomeric free base. In saturated solutions, the apparent solubility in alkaline pH would be elevated due to the presence of the dimer. The effect of that would be a lower pKa and reverse pKa cosolvent dependence – the behaviour we have noticed in CFZ aqueous solutions. These findings are of paramount importance for understanding of CFZ speciation and the future progress in developing its improved formulations which is the subject of our ongoing studies

Ispitivanje kompatibilnosti nateglinida s pomoćnim tvarima u razvoju tableta nateglinida za trenutno oslobađanje

Experiments were done to assess the compatibility of nateglinide with selected excipients in the development of immediate release tablets of nateglinide by thermal and isothermal stress testing (IST) techniques. To evaluate the drug-excipient compatibility, different techniques such as differential scanning calorimetric (DSC) study, infra-red (IR) spectrophotometric study and isothermal stress testing were adopted. The results of DSC study showed that magnesium stearate exhibited some interaction with nateglinide. However, the results of IR, and IST studies showed that all the excipients used in the formula were compatible with nateglinide. Optimized formulations developed using the compatible excipients were found to be stable over 3 months of accelerated stability studies (40 ± 2 C and 75 ± 5 % RH). Overall, compatibility of excipients with nateglinide was successfully evaluated using a combination of thermal and IST methods and the formulations developed using the compatible excipients were found to be stable.Koristeći termičke metode kao što su diferencijalna pretražna kalorimetrija (DSC) i infra-crvena spektrofotometrija (IR), te izotermička stres-testiranja (IST) ispitana je kompatibilnost nateglinida s izabranim ekscipiensima u razvoju tableta nateglinida za trenutno oslobađanje. Rezultati DSC ispitivanja pokazala su da magnezijev stearat stupa u određenu interakciju s nateglinidom. Međutim, IR i IST ispitivanja pokazuju da su svi upotrijebljeni ekscipiensi kompatibilni s nateglinidom. Optimirana formulacija bila je stabilna preko 3 mjeseca u testovima ubrzanog starenja (40 ± 2 C i 75 ± 5 % RH). Kompatibilnost ekscipiensa s nateglinidom uspješno je evaluirana koristeći kombinaciju termičke i IST metode, a formulacije razvijene koristeći kompatibilne ekscipiense bile su stabilne

Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

OBJECTIVE—Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs

Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide) Micelles as Nanocarriers for Oral Delivery of Cyclosporine A

A series of monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) diblock copolymers were designed according to polymer–drug compatibility and synthesized, and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA). CyA was efficiently encapsulated into the micelles with nanoscaled diameter ranged from 60 to 96 nm with a narrow size distribution. The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal fluids. The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles. The enhanced intestinal absorption of CyA-loaded polymeric micelles, which was comparable to the commercial formulation of CyA (Sandimmun Neoral®), was found. These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug