Due to their unique properties, such as controlled drug release and improved bioavailability, polymeric microparticles and nanoparticles (MPs and NPs) have gained considerable interest in the pharmaceutical industry. Nevertheless, the high costs associated with biodegradable polymers and the active pharmaceutical ingredients (APIs) used for treating serious diseases, coupled with the vast number of API-polymer combinations, make the search for effective API-polymer MPs and NPs a costly and time-consuming process. In this work, the correlation between the compatibility of selected model APIs (i.e., ibuprofen, naproxen, paracetamol, and indomethacin) with poly(lactide-co-glycolide) (PLGA) derived from respective binary phase diagrams and characteristics of prepared MPs and NPs, such as the drug loading and solid-state properties, was investigated to probe the possibility of implementing the modeling of API-polymer thermodynamic and kinetic phase behavior as part of rational design of drug delivery systems based on MPs and NPs. API-PLGA-based MPs and NPs were formulated using an emulsion-solvent evaporation technique and were characterized for morphology, mean size, zeta potential, drug loading, and encapsulation efficiency. The solid-state properties of the encapsulated APIs were assessed using differential scanning calorimetry and X-ray powder diffraction. The evaluated compatibility was poor for all considered API-PLGA pairs, which is in alignment with the experimental results showing low drug loading in terms of amorphous API content. At the same time, drug loading of the studied APIs in terms of amorphous content was found to follow the same trend as their solubility in PLGA, indicating a clear correlation between API solubility in PLGA and achievable drug loading. These findings suggest that API-polymer phase behavior modeling and compatibility screening can be employed as an effective preformulation tool to estimate optimum initial API concentration for MP and NP preparation or, from a broader perspective, to tune or select polymeric carriers offering desired drug loading.
Food and chemical toxicology, ISSN 0278-6915 Supplement Vol. 30
138 s. : obr., přeruš.bibliogr.
- Keywords
- látky vonné - složení - monografie,
- Conspectus
- Chemie. Mineralogické vědy
- NML Fields
- chemie, klinická chemie
- biologie
- toxikologie
Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.
- MeSH
- Chemistry, Pharmaceutical * MeSH
- Humans MeSH
- Microscopy MeSH
- Tablets chemistry therapeutic use MeSH
- Temperature MeSH
- Particle Size MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Knowledge of the active pharmaceutical ingredient (API) solubility in a polymer is imperative for successful amorphous solid dispersion design and formulation but acquiring this information at storage temperature is challenging. Various solubility determination methods have been established, which utilize differential scanning calorimetry (DSC). In this work, three commonly used DSC-based protocols [i.e., melting point depression (MPD), recrystallization, and zero-enthalpy extrapolation (Z-EE)] and a method that we have developed called "step-wise dissolution" (S-WD) were analyzed. For temperature-composition phase diagram construction, two glass-transition temperature equations (i.e., those of Gordon-Taylor and Kwei) and three solid-liquid equilibrium curve modeling approaches [i.e., the Flory-Huggins model, an empirical equation, and the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS)] were considered. Indomethacin (IND) and Kollidon 12 PF (PVP K12) were selected as the API and polymer, respectively. An annealing time investigation revealed that the IND-PVP K12 dissolution process was remarkably faster than demixing, which contradicted previously published statements. Thus, the recrystallization method overestimated the solubility of IND in PVP K12 when a 2-h time of annealing was set as the benchmark. Likewise, the MPD and Z-EE methods overestimated the API solubility because of unreliable IND melting endotherm evaluation at lower API loadings and a relatively slow heating rate, respectively. When the experimental results obtained using the S-WD method (in conjunction with the Kwei equation) were applied to the PC-SAFT EOS, which was regarded as the most reliable combination, the predicted IND solubility in PVP K12 at T = 25 °C was approximately 40 wt %. When applicable, the S-WD method offers the advantage of using a limited number of DSC sample pans and API-polymer physical mixture compositions, which is both cost- and time-effective.
- MeSH
- Models, Chemical MeSH
- Calorimetry, Differential Scanning MeSH
- Chemistry, Pharmaceutical methods MeSH
- Crystallization MeSH
- Polymers chemistry MeSH
- Excipients chemistry MeSH
- Solubility MeSH
- Transition Temperature MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
Although the fragmentation of the active pharmaceutical ingredient (API) is a phenomenon that is mentioned in many literature sources, no well-suited analytical tools for its investigation are currently known. We used the hot-stage microscopy method, already presented in our previous work, and studied the real fragmentation of the tadalafil particles in model tablets which were prepared under different compaction pressures. The morphology, spectral imaging and evaluation of plastic and elastic energies were also analyzed to support the hot-stage method. The prepared blend of tadalafil and excipients was compacted under a several forces from 5 to 35 kN to reveal the trend of fragmentation. The exact fragmentation of tadalafil with increased compaction pressure was revealed by the hot-stage microscopic method and it was in good agreement with plastic and elastic energies. Conversely, spectral imaging, which is being used for this analysis, was considered to be inaccurate methodology as mainly agglomerates, not individual particles, were measured. The availability of the hot-stage microscopic method equips pharmaceutical scientists with an in vitro assessment technique that will more reliably determine the fragmentation of the API in finished tablets and the behavior of the particles when compacted.
