Design of a Stable Coamorphous System Using Lactose as an Antiplasticizing Agent for Diphenhydramine Hydrochloride with a Low Glass Transition Temperature.

Coamorphous systems comprising small molecules are emerging as counterparts to polymeric solid dispersions. However, the glass transition temperatures (Tgs) of coamorphous materials are relatively low because of the lack of polymeric carriers with higher Tgs. This study aimed to investigate the applicability of lactose (LAC) as an antiplasticizing coformer to a coamorphous system. Diphenhydramine hydrochloride (DPH) was selected as a model drug (Tg = 16 °C). Differential scanning calorimetry showed a comelting point in addition to a decrease in the neat melting points depending on the composition of the physical mixtures, suggesting that the mixture of DPH-LAC was eutectic. The melting point of the eutectic mixture was calculated according to the Schröder-van Laar equation. The heat of fusion of the eutectic mixture was maximized at a 70:30 molar ratio of DPH to LAC; at this point, the melting peaks of the pure components disappeared. The heat flow profiles following the melting and cooling of DPH-LAC physical mixtures at the ratios from 10:90 to 90:10 showed a single Tg, suggesting the formation of a coamorphous system. Lactose showed a Tg of over 100 °C, and the Tg of DPH increased with the molar ratio of LAC; it was 84 °C at a 10:90 molar ratio of DPH to LAC. The Raman image indicated the formation of a homogeneous dispersion of DPH and LAC in the coamorphous system. Peak shifts in the infrared spectra indicated the presence of intermolecular interactions between the amino group of DPH and the hydroxyl group of LAC. Principal component analysis of the infrared spectra revealed a significant change at the 70:30 molar ratio of DPH to LAC, which was in agreement with the results of the thermal analysis. A stability test at 40 °C revealed rapid crystallization of the supercooled liquid DPH. The coamorphous samples containing 10-50% of LAC remained in an amorphous state for 21 days, and no crystallization was observed for the samples containing >60% of LAC for 28 days. The relatively lower Tg (less than 40 °C) of the coamorphous system containing 10-50% of LAC might have caused crystallization during storage. These findings indicate that LAC, which is a safe and widely used pharmaceutical excipient, can be applied to coamorphous systems as an antiplasticizing coformer.

The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro-in vivo correlation of nanocrystals.

Nanocrystal formulation is a well-established approach for improving oral absorption of poorly water-soluble drugs. However, it is difficult to predict the in vivo performance of nanocrystal formulations from in vitro dissolution studies. The object of the present study was to investigate the in vitro-in vivo correlation of nanocrystal formulations of different particle sizes. A microsuspension and three nanosuspensions with different particle sizes for model drugs, fenofibrate and megestrol acetate, were prepared. In the comparison between the microsuspension and the nanosuspension having the smallest particle sizes, drug permeation rates from the nanosuspension were about 3-fold higher in the dissolution-permeation study. On the other hand, the solubility enhancement effect due to nanocrystal formation was only up by 1.4-fold, suggesting that nanocrystal formulations dramatically improved not the solubility but the apparent permeability. The oral absorption rate in rats increased with particle size reduction. There were positive and very strong correlations (R2 > 0.95) between the in vitro permeation rate and in vivo maximum absorption rate. We concluded that the enhanced permeability rate due to nanocrystal formation is the main factor for improving oral absorption, and the in vitro dissolution-permeation study could be useful for predicting oral absorption enhancement of nanocrystal formulations.

In-situ dissolution and permeation studies of nanocrystal formulations with second-derivative UV spectroscopy.

One of the most difficult challenges in developing nanocrystal formulations is to determine the dissolution behavior of nanocrystal suspensions (nanosuspensions), which occurs within seconds. Mefenamic acid (MFA) is a poorly soluble drug thought to limit the dissolution rate for membrane permeation. In this study, in-situ dissolution-permeation studies of a nanosuspension of mefenamic acid (MFA) were carried out using second-derivative UV spectroscopy. This method enabled us to distinguish between the concentrations of dissolved MFA and nano-suspended MFA via in-situ measurement and showed an improved dissolution rate of the nanosuspension compared to that of the microsuspension. The dissolution-permeation study with second-derivative UV spectroscopy revealed that the improved dissolution rate due to nanosized MFA resulted in an increase in the permeated amount of MFA. In addition, the solubility of MFA determined by HPLC after filtration with a 0.02-µm filter indicated that enhanced solubility due to nanosizing also improves the permeability of MFA. Therefore, we concluded that the solubility and dissolution rate enhancements attained by nanosizing would be key factors in increasing membrane transportation of MFA. These novel in-situ dissolution-permeation studies using second-derivative UV spectroscopy offer considerable promise for developing and characterizing nanocrystal formulations.

Co-amorphous Formation Induced by Combination of Tranilast and Diphenhydramine Hydrochloride.

In this study, we investigated the formation of a co-amorphous system of tranilast (TRL) and diphenhydramine hydrochloride (DPH), which are drugs used for treating allergies and inflammation. The crystallization from undercooled melts of the drugs and drug mixtures was evaluated by thermal analysis. Both drugs in the amorphous state underwent crystallization on heating, although the mixture remained in the amorphous state, indicating the formation of a co-amorphous system. The physicochemical properties of co-amorphous TRL-DPH prepared by the melting-cooling process were studied. The glass transition temperature of co-amorphous TRL-DPH deviated from the theoretical value. The enthalpy relaxation rate of the amorphous drugs, which reflected the molecular mobility, was reduced by the formation of a co-amorphous system. The intermolecular interactions between TRL and DPH in the co-amorphous system were measured by the change in the IR spectra. These results were consistent with the high physical stability. The co-amorphous sample remained in the amorphous state for over 30 days at 40°C, whereas the amorphous drugs showed rapid crystallization. Our findings demonstrate that TRL and DPH form a co-amorphous system, which dramatically decreases their crystallization without an excipient.

A novel application of α-glucosyl hesperidin for nanoparticle formation of active pharmaceutical ingredients by dry grinding.

The effectiveness of α-glucosyl hesperidin (Hsp-G) as a novel grinding aid for the preparation of drug nanoparticles by dry grinding was investigated. Poorly water-soluble drugs and Hsp-G were mixed at a weight ratio of 1/5 and ground for 60 min by a vibrational ball mill. It was evident that all poorly water-soluble drugs used in this study formed nanoparticles after the ground mixtures were dispersed into distilled water. The dissolution profile of glibenclamide from the ground mixtures of glibenclamide/Hsp-G showed dramatic improvement from that of untreated drug crystals. Administration of the ground mixture of glibenclamide/Hsp-G to rats resulted in a significantly higher rate of decrease in blood glucose levels than that of untreated glibenclamide. The area above the time-curve of plasma-glucose concentrations using the ground mixture of glibenclamide/Hsp-G was 6-fold higher than that using untreated glibenclamide. The improved dissolution rate due to nanoparticle formation of glibenclamide, induced by co-grinding with Hsp-G, was responsible for this improvement.

Transglycosylated stevia and hesperidin as pharmaceutical excipients: dramatic improvement in drug dissolution and bioavailability.

The capability of transglycosylated materials, α-glycosyltransferase-treated stevia (Stevia-G) and α-glycosyl hesperidin (Hsp-G), to enhance the bioavailability of poorly water-soluble drugs was investigated. Spray-dried particles (SDPs) of drug/transglycosylated material, such as, flurbiprofen (FP)/Stevia-G, probucol (PRO)/Stevia-G, FP/Hsp-G, and PRO/Hsp-G were prepared. All SDPs showed pronounced improvement in both dissolution rate and apparent drug solubility. The amount of dissolved PRO was significantly improved to that of untreated PRO crystals when prepared as SDPs of PRO/Stevia-G or PRO/Hsp-G. There was no cytotoxicity to Caco-2 cells at levels of 10% Stevia-G or Hsp-G solution. Values for the area under the plasma concentration-time curve (AUC) of untreated PRO, SDPs of PRO/Hsp-G and PRO/Stevia-G after oral administration to rats were 4.94±2.06, 26.08±4.52 and 48.79±9.97µgh/mL, respectively. Interestingly, AUC values in cases of the FP system were in the order of untreated FP

Improvement of dissolution and absorption properties of poorly water-soluble drug by preparing spray-dried powders with alpha-glucosyl hesperidin.

The feasibility of alpha-glucosyl hesperidin (Hsp-G) to improve the dissolution and bioavailability of poorly water-soluble drug was investigated. A spray-dried powder (SDP) of Hsp-G and flurbiprofen (FP), an acidic drug (pK(a)=3.78) with low water solubility, was prepared by a spray-drying method. Powder X-ray diffraction analysis revealed the conversion of FP from the crystal to the amorphous form when dispersed in Hsp-G. The SDPs of FP/Hsp-G resulted in pronounced improvement in both the dissolution rate and solubility of FP. The apparent solubility of FP in hydrochloric acid solution (pH 1.2) was improved by 10-fold more than untreated FP crystals when prepared as SDPs in Hsp-G. The bioavailability of FP from the prepared SDPs was evaluated in vivo after oral administration to rats, in comparison with the untreated FP crystals. The results revealed 2.5- and 2.8-fold improvement in the C(max) and AUC values, respectively, after oral administration of the SDPs of FP/Hsp-G. In conclusion, Hsp-G is a potentially safe material to enhance the dissolution and absorption of poorly water-soluble drugs.