Efavirenz, an antiretroviral drug, is a class 2 according to the biopharmaceutics classification system. Many dissolution enhancement systems have been tried and our group had success using wet milling to decrease particle size and granules were obtained by spray and freeze drying. In this paper we present data related to the upgrade in the process, raising the solids concentration in the suspension from 10 to 50% (m/v) and changing the drying step for a fluid bed granulation. After that, tablets were obtained. Granules and tablets were fully evaluated and a pharmacokinetic study was also performed with the granules. By powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR) it was possible to prove that there was no phase transition in the sample after milling and drying. Dissolution efficiency of 4 from 5 granules was higher than 90%, considering 83% for the raw material. Tablets were technically approved but the dissolution was impacted and just 2 out of 11 showed results > 80%. A high enhancement in the bioavailability was also observed, around 172%. So, it is possible to conclude that efavirenz microcrystals with enhanced dissolution and bioavailability can be formulated into tablets and are a viable system to develop a new drug product. Efavirenz process 1 50 m/v mv m v (m/v granulation Xray X ray PXRD (PXRD FTIR (FTIR 90 90% 83 material 80 80% observed 172 172% So product 9 8 17

Abstract The pharmaceutical industry is mostly dedicated to the production of drugs in solid forms such as tablets and capsules with active ingredients and excipients in the same physical state. Regarding the regulatory requirements for the analytical development and implementation of solid-state analyses, internationally recognized pharmaceutical compendia play an important role. However, the information contained in the various general chapters and monographs differs from each other, especially in countries that have national pharmacopeias, such as Brazil. Thus, the main objective of this work is to critically evaluate, based on the technical-scientific literature, the harmonization of the United States, European, British, Japanese and Brazilian pharmacopeias with respect to the following analytical techniques used for solid-state characterization: X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and infrared and Raman spectroscopies. The working principle of each analytical technique, as well as the methodological parameters that impact the implementation of the analyses, are detailed. The results indicate that, in terms of solid-state characterization analysis, the adoption of unified scientific standards and principles is not yet a reality for all compendia. Additionally, the lack of harmonization between BrazP and the other compendia is especially significant, considering that ANVISA is an ICH member, the main entity responsible for promoting harmonization. state solidstate analyses role However Brazil Thus evaluate technicalscientific technical literature States European British Xray X ray diffraction calorimetry analysis spectroscopies technique detailed Additionally significant member

Abstract Dissolution is a key step in the uptake of oral drugs. In order to compare the behaviour of the dissolution of two formulations, the dissolution profile test was used. This assay must be discriminative and should mimic in vivo conditions. Many dissolution media described in pharmacopoeias are not predictive of bioavailability. Due to this, biorelevant media are used as an alternative to solve this problem. The objective of this work is to evaluate the relevance of biorelevant dissolution media to predict in vivo drug dissolution. For this, a bibliographic search was carried out in scientific databases. The search was first performed for articles verifying the physicochemical properties of human gastrointestinal fluids. Subsequently, a comparison was made between the properties of gastrointestinal fluids and those of biorelevant and pharmacopoeial media. Finally, the results of bioequivalence studies and dissolution profile tests in biorelevant media described in the literature were compared. The results revealed that there are a few publications that have analysed some physicochemical properties of gastrointestinal fluids. In addition, high variability was observed for some properties. Regarding the comparison of these properties with pharmacopoeial media and biorelevant media, the analysis showed that the biorelevant media are more similar to gastrointestinal fluids than the pharmacopoeial media. Finally, the in vitro dissolution profile results were similar to the results obtained in vivo. Thus, biorelevant media may be useful for analysing dissolution profiles.

Abstract Efavirenz is one of the most commonly used drugs in HIV therapy. However the low water solubility tends to result in low bioavailability. Drug nanocrystals, should enhance the dissolution and consequently bioavailability. The aim of the present study was to obtain EFV nanocrystals prepared by an antisolvent technique and to further observe possible effect, on the resulting material, due to altering crystallization parameters. A solution containing EFV and a suitable solvent was added to an aqueous solution of particle stabilizers, under high shear agitation. Experimental conditions such as solvent/antisolvent ratio; drug load; solvent supersaturation; change of stabilizer; addition of milling step and solvents of different polarities were evaluated. Suspensions were characterized by particle size and zeta potential. After freeze- dried and the resulting powder was characterized by PXRD, infrared spectroscopy and SEM. Also dissolution profiles were obtained. Many alterations were not effective for enhancing EFV dissolution; some changes did not even produced nanosuspensions while other generated a different solid phase from the polymorph of raw material. Nevertheless reducing EFV load produced enhancement on dissolution profile. The most important modification was adding a milling step after precipitation. The resulting suspension was more uniform and the powder presented grater enhancement of dissolution efficacy.

Abstract Introduction: The immediate-release solid oral products containing very soluble and permeable drugs are candidates for the biowaiver process. This work aims to compare in vitro, in silico, and in vivo data to establish if previously published prednisone oral tablet formulations are biowaiver candidates. Method: To achieve this goal, permeation studies were conducted on Caco-2 cells. A previous bioequivalence study between the test and the reference drug product was applied on an in silico evaluation using Gastroplus® to assess the bioequivalence of two other previously proposed formulations. Results: The apparent permeability coefficient for prednisone presented a value of 3.69 x 10-5 cm/s in 180 minutes. The bioequivalence study shows that the tested and reference product was equivalent. The in silico simulations successfully predicted the pharmacokinetics of the tested and the other two formulations since they were validated with the in vivo study. Both exhibit the same plasma concentration vs. time profiles. Conclusions: Through the in silico results, it is possible to infer that the other two formulations tested may be bioequivalent concerning the reference product. This result may be helpful in biowaiver requesting. Toward to reduce costs and the use of human beings in bioequivalence studies, this approach could be an essential way to work in the pharmaceutical industry.

Resumen Introducción: Los productos orales sólidos de liberación inmediata que contienen fármacos muy solubles y permeables son candidatos para el proceso de bioexención. Este trabajo tiene como objetivo comparar datos in vitro, in silico e in vivo para establecer si las formulaciones de comprimidos orales de prednisona publicadas anteriormente son candidatas a la bioexención. Método: Para lograr este objetivo se realizaron estudios de permeación en células Caco-2. Se aplicó un estudio de bioequivalencia previo entre la formulación de prueba y el medicamento de referencia en una evaluación in silico utilizando Gastroplus® para evaluar la bioequivalencia de otras dos formulaciones propuestas anteriormente. Resultados: El coeficiente de permeabilidad aparente para prednisona presentó un valor de 3,69 x 10-5 cm/s en 180 minutos. El estudio de bioequivalencia muestra que el producto probado y de referencia era equivalente. Las simulaciones in silico predijeron con éxito la farmacocinética de las formulaciones probadas y las otras dos, ya que fueron validadas con el estudio in vivo . Ambos exhiben los mismos perfiles de concentración plasmática frente a tiempo. Conclusiones: A través de los resultados in silico , es posible inferir que las otras dos formulaciones ensayadas pueden ser bioequivalentes respecto al producto de referencia. Este resultado puede ser útil en la solicitud de bioexenciones. Para reducir los costos y el uso de seres humanos en los estudios de bioequivalencia, este enfoque podría ser una forma esencial de trabajar en la industria farmacéutica.

ABSTRACT Solid dosage forms for oral use, particularly tablets, are the most highly used dosage forms in therapy because they are easily administered, have high productivity and relatively low cost and provide a more stable drug to form a semi-solid net. Numerous parameters influence the quality of the final dosage form. In this study, the dissolution profile of 20-mg prednisone tablets bioequivalent to the reference product and three test formulations were evaluated using stability testing. During the study, prednisone tablets and the active pharmaceutical ingredient (API) prednisone from two different manufacturers were characterized with respect to their physical and physicochemical properties. The results showed that the dissolution profiles of the test batches and the reference product did not retain pharmaceutical equivalence throughout all the stability study. Notably, both samples of API prednisone were of the same crystal form, and any phase transition that occurred during the study could not be attributed to dissolution variation during stability.