The influence mechanism of biorelevant media on the dissolution of active pharmaceutical ingredients (APIs) is the key to their formulation design. The dissolution kinetics of naproxen (NAP) and indomethacin (IND) in biorelevant media was systematically investigated. The dissolution mechanism was analyzed by chemical potential gradient model to explore the influence of surfactant type, pH and ionic strength. Hexadecyl trimethyl ammonium bromide (CTAB) is superior to sodium dodecyl sulfate (SDS) in promoting the dissolution of NAP and IND by increasing the solubility and accelerating the surface reaction processes. The electrostatic repulsion between SDS and NAP and IND with the same negative charge facilitates the diffusion of API, while the mutual attraction between CTAB and NAP and IND is not conducive to diffusion. High pH was favorable for the dissolution of acidic NAP and IND, as the simultaneous increase in solubility, surface reaction constant, and diffusion constant. High ionic strength was beneficial for the surface reaction of NAP and IND, but hindered their diffusion. It was shown that the modeling results were in conformity with the in vitro experimental data. These results are expected to provide theoretical supports for the design of biorelevant media and pharmaceutical formulations in the pharmaceutical development.

The solubility of active pharmaceutical ingredients (APIs) in biorelevant media is important fundamental data for API formulation design and contributes to better evaluation of in vivo dissolution kinetics. However, these data are mainly determined by experimental measurements, which is rather time and cost consuming. Therefore, it is essential to develop a novel theoretical strategy to describe and predict API solubility in biorelevant media. In this work, the solubilization effect of micelle and the effect of pH as well as ion components on the solubility of naproxen and indomethacin were determined experimentally. A micellar solubilization model and pH-dependent solubility model were proposed to model the effect of various micelles and pH (including buffer components) on API aqueous solubility, respectively. The combination of the two model successfully described the biorelevant solubility of APIs as function of temperature. The proposed strategy could provide insights into the mechanisms of micelle and different pH regulated by different buffer components on API solubility and could accurately describe the solubility of APIs in biorelevant media. This work is expected to provide theoretical guidance for API formulation development.

This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an iterative calibration routine to describe the behavior of the powder in the roller compactor and improves the predictive quality of the mechanistic models at low and high-throughput. The model has been validated with an experimental design of experiments of two ibuprofen formulations. The predicted sweet spots in the operating space are in good agreement with the experimental results.

In this work, amorphous paracetamol/Eudragit® formulations for four Eudragit® (polymeric excipients) were prepared by spray drying technique. The simultaneous dissolution kinetics of paracetamol and Eudragit® from these formulations were measured as function of pH in vitro using a rotating disk system (USP II). Paracetamol dissolution mechanisms were analyzed by comparing the dissolution rates of paracetamol and excipient. It was found that a controlled paracetamol dissolution was achieved from Eudragit® L 100-55 and Eudragit® E PO formulations at pH 5.0, 6.5, and 7.2. Furthermore, a controlled paracetamol dissolution was also achieved from Eudragit® L 100 formulations at pH 6.51 and 7.27 as well as from Eudragit® S 100 formulations at pH 7.27. Paracetamol dissolution rates were controlled by both paracetamol and excipient from Eudragit® L 100 and S 100 formulations at other pH values. Moreover, a chemical-potential-gradient model combined with PC-SAFT was used to model the dissolution kinetics of PARA from these formulations in good accordance with the experimental data.

In this work, the dissolution profiles of different crystalline active pharmaceutical ingredients (APIs), which show a diverse water solubility (paracetamol>hydrochlorothiazide>trimethoprim>naproxen>indomethacin>cinnarizine) were measured in water at different temperatures and stirring speeds using a rotating disk system. Meanwhile, the dissolution mechanism of these APIs was analyzed by using a two-step chemical-potential-gradient model. The solubilities and activity coefficients of the investigated APIs were calculated by using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). It was found out, that the dissolution mechanism of different crystalline APIs in water can be different dependent on their water solubilities. Additionally, an increase in both, the surface reaction and diffusion rate constants for all investigated crystalline APIs was observed with an increase in temperature and stirring speed. By the use of linear correlations between the API surface reaction and diffusion rate constants with the temperature and stirring speed, the dissolution profiles of the selected APIs could be predicted as function of temperature and stirring speed with high accuracy compared to the experimental data.

The release kinetics of indomethacin (IND) and hydrochlorothiazide (HCT) from drug/PLGA formulations with different copolymer composition and molecular weight of PLGA were measured in vitro by using a rotating disk system (USP II). The release mechanism of IND and HCT from their PLGA formulations was analyzed using a chemical-potential-gradient model combined with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Furthermore, the release kinetics of IND and HCT from the PLGA formulations with different copolymer composition and molecular weight of PLGA were correlated and predicted in good accordance with the experimental data. It was found that the chemical-potential-gradient model combined with the PC-SAFT helped to understand the drug release mechanism from the drug/PLGA formulations. It also well correlated and predicted the drug release kinetics as function of copolymer composition and molecular weight of PLGA as well as of drug type. It helps to save time and costs for determination of the long-term drug release kinetics, especially for sustained drug release as obtained from the drug/PLGA formulations in this work. © 2016 American Institute of Chemical Engineers AIChE J , 62: 4055–4065, 2016

In this work, a two-step chemical-potential-gradient model based on nonequilibrium thermodynamic principles was developed to investigate the dissolution mechanism of crystalline active pharmaceutical ingredients (APIs). The perturbed-chain statistical associating fluid theory was used to calculate the required solubilities and chemical potentials of the investigated APIs. The statistical rate theory was used to describe the mass-transfer rate of the APIs at the solidliquid interface during the dissolution process. Dissolution profiles of indomethacin, naproxen, and glibenclamide in water and in buffered solutions at pH 5.0, 6.5, and 7.2 were measured using a rotating-disk system (USP II). The specific dissolution mechanisms of the APIs, such as surface reaction and diffusion, were analyzed by applying the proposed model to identify the rate-controlling step. The results show that the dissolution mechanisms of indomethacin, naproxen, and glibenclamide change with varying pH values of the solution medium. On the basis of the calculated rate constants, the dissolution profiles were modeled with a high degree of accuracy when compared with the experimental data.

In this work, solubilities and dissolution profiles of the active pharmaceutical ingredients (APIs) indomethacin and naproxen were measured in water in the presence of one excipient out of polyethylene glycol (PEG) 2000, 6000 and 12000, polyvinylpyrrolidone (PVP) K 25 and mannitol. It was found that the solubility of indomethacin and naproxen was increased with an addition of the selected excipients, which was also predicted by the perturbed-chain statistical associating fluid theory (PC-SAFT). The two-step chemical-potential-gradient model was applied to investigate the dissolution mechanism of indomethacin and naproxen in water in the presence of the excipient. It was found that the dissolution mechanisms of indomethacin and naproxen were changed by the presence of excipients. Although the solubility of the API was increased by the addition of excipients, the dissolution rate of the API was decreased in some cases. This was mainly due to the combination of the molecular interactions between the API and the polymer with the influence of the excipients on the kinetic part (rate constant of the surface reaction or diffusion of the API or both) of API dissolution as function of PEG molar mass as well as of the API type. Based upon the determined rate constants, the dissolution profiles were modeled with a high accuracy compared with the experimental data.

The solubility of cinnarizine has been investigated in acetonitrile, butyl acetate, 1-butanol, 2-propanol, and water in a temperature range from 288.15 K to 313.15 K. During crystallization from these solvents two different crystal morphologies of cinnarizine were observed. The caloric properties (melting temperature, melting enthalpy, and the difference in the heat capacity of solid and liquid cinnarizin) were measured by differential scanning calorirnetry. The temperature-dependent solubility of cinnarizine in different organic solvents and in water was modeled using the perturbed-chain statistical associating fluid theory and was in good agreement with the experimental data.

For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method.

PURPOSE:To analyze the dissolution mechanism of solid dispersions of poorly water-soluble active pharmaceutical ingredients (APIs), to predict the dissolution profiles of the APIs and to find appropriate ways to improve their dissolution rate.METHODS:The dissolution profiles of indomethacin and naproxen from solid dispersions in PVP K25 were measured in vitro using a rotating-disk system (USP II). A chemical-potential-gradient model combined with the thermodynamic model PC-SAFT was developed to investigate the dissolution mechanism of indomethacin and naproxen from their solid dispersions at different conditions and to predict the dissolution profiles of these APIs.RESULTS:The results show that the dissolution of the investigated solid dispersions is controlled by dissolution of both, API and PVP K25 as they codissolve according to the initial API loading. Moreover, the dissolution of indomethacin and naproxen was improved by decreasing the API loading in polymer (leading to amorphous solid dispersions) and increasing stirring speed, temperature and pH of the dissolution medium. The dissolution of indomethacin and naproxen from their amorphous solid dispersions is mainly controlled by the surface reaction, which implies that indomethacin and naproxen dissolution can be effectively improved by formulation design and by improving their solvation performance.CONCLUSIONS:The chemical-potential-gradient model combined with PC-SAFT can be used to analyze the dissolution mechanism of solid dispersions and to describe and predict the dissolution profiles of API as function of stirring speed, temperature and pH value of the medium. This work helps to find appropriate ways to improve the dissolution rate of poorly-soluble APIs.

In this paper, the intrinsic dissolution profiles of naproxen (NAP) at pH values of 1.5 and 3.0 and of trimethoprim (TMP) at pH values of 1.5, 3.0, 5.0, 6.5 and 7.2 were measured. Meanwhile, the dissolution profiles of NAP and TMP from cylindrical tablets were measured at different temperatures (298.15K, 305.15K, 301.15K and 310.15K) and stirring speeds (50rpm, 100rpm and 150rpm) as well as at different pH values (1.5, 3.0, 5.0, 6.5 and 7.2). Additionally the pH-dependent solubilities of both APIs were measured and modeled. The chemical-potential-gradient model combined with the perturbed-chain statistical associating fluid theory (PC-SAFT) was applied to predict the dissolution profiles of the cylindrical tablets of NAP and TMP under different conditions based on the analysis of their intrinsic dissolution profiles as well as on the determination of the surface-area reduction of the API tablets during dissolution. It was shown that the predicted dissolution profiles of the tablets under different conditions were in a good accordance with the experimental findings.

As the morphology of spray dried aqueous mannitol solutions is strongly influenced by the scale of the used spray dryer or more correctly by the droplet size generated in the spray dryer the purpose of this work is to carefully study and compare the morphologies and underlying particle formation mechanisms on lab and pilot scale. Therefore drying experiments of 15% [w/w] aqueous mannitol solutions were performed on a lab and pilot scale spray dryer at different outlet temperatures. The obtained spray dried products are intended to be used as carrier particles for pulmonary drug delivery. In order to show that the morphology is highly dependent on the initial droplet size, irrespective of the size of the used spray dryer, droplets of different size were dried in the pilot scale spray dryer at different air outlet temperatures. Additionally the influence of feed temperature on particle morphology was studied.For small droplets crystallization from a highly viscous liquid or even water-free melt is observed, leading to rough particles at high outlet temperatures and smooth particles at low temperatures. When drying larger droplets, however crystallization obviously starts from a more diluted solution leading to rougher surfaces, containing larger single crystals at lower outlet temperatures than at higher ones. For large droplets an increase in the mannitol solution feed temperature leads to particles of comparably rougher surface. No influence of feed temperature was observed for smaller droplets. (C) 2013 Elsevier B.V. All rights reserved.

The influence of the atomization method on the product homogeneity in spray drying is discussed. For identical drying histories at individual particles, a narrow drop size distribution has to be achieved in order to produce a homogeneous powder. Spray drying experiments with aqueous solutions of polyvinylpyrrolidon and D-Mannitol were carried out. For generation of narrow distributed droplets a laminar operated rotary atomizer is applied. Homogeneous particle properties of the powders were achieved. However, this kind of atomization requires special drying gas distribution. A possible geometry for a proper heating gas distribution is presented.