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Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration.

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular “Chopin Tavares de Lima” (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.

Abstract The second generation of H1 antihistamines from the piperidine group are often used for treating allergic diseases due to their action on histaminic receptors, the primary mediator of allergy. Moreover, the antihistamines have anti-inflammatory action, mediated through platelet-activating factor blocking activity. A simple and rapid capillary zone electrophoresis method was developed and validated for the determination of loratadine (LOR) and rupatadine (RUP) in tablets. The analyses were carried out using a fused silica capillary of 50.2 cm (40 cm effective length), 75 µm i.d. The background electrolyte was composed of boric acid 35 mmol/L, pH 2.5. Voltage of 20 kV, hydrodynamic injection of 3447.3 Pa for 3s, temperature at 25 ºC, and UV detection at 205 nm were applied. Electrophoretic separation was achieved at 1.8 and 2.8 min for RUP and LOR, respectively. The method was linear for both drugs in a range of 50.0 to 400.0 μg/mL (r>0.99). The limits of detection and quantification were 46.37 and 140.52 μg/mL, for LOR and 29.60 and 89.69 μg/mL for RUP respectively. The precision was less than 5.0 % for both drugs. The average recovery was approximately 100 %. The proposed novel method can significantly contribute to the rapid detection of counterfeit products and in quality control of drug products containing antihistamines.

Bacterial conjunctivitis significantly impacts public health, including more than one-third of eye diseases reported worldwide. It is an infection caused by various aerobic and anaerobic bacteria and is highly contagious. Therefore, it has a high incidence of bacterial resistance to the antibiotics commonly used for treatment. Among the most recent antibiotics, besifloxacin is a fourth-generation fluoroquinolone antibiotic indicated exclusively for topical ophthalmic use. Due to its importance in treating bacterial conjunctivitis and its low solubility in water, limiting its efficacy, a nanotechnology-based drug delivery preparation was developed to overcome this hurdle. Besifloxacin nanocrystals were prepared by small-scale wet milling and response surface methodology, using Povacoat® as a stabilizer. The particle’s average hydrodynamic diameter (Z-ave) was approximately 550 nm (17 times smaller than raw material), with a polydispersity index (PdI) of less than 0.2. The saturation solubility increased about two times compared to the raw material, making it possible to increase the dissolution rate of this drug substance, potentially improving its bioavailability and safety. The optimized preparation was stable under an accelerated stability study (90 days). The Z-ave, PZ, PdI, and content did not alter significantly during this period. Furthermore, the 0.6% m/m besifloxacin nanocrystals at the maximum dose and the Povacoat® stabilizer did not show toxicity in Galleria mellonella larvae. The innovative ophthalmic preparation minimum inhibitory concentration (MIC) was 0.0960 µg/mL and 1.60 µg/mL against Staphylococcus aureus and Pseudomonas aeruginosa, respectively, confirming in vitro efficacy. Therefore, besifloxacin nanocrystals revealed the potential for reduced dosing of the drug substance, with a minor occurrence of adverse effects and greater patient adherence to treatment.

Raman spectroscopy is a very promising technique increasingly used in the pharmaceutical industry. Due to its development and improved instrumental versatility achieved over recent decades and through the application of chemometric methods, this technique has become highly precise and sensitive for the quantification of drug substances. Thus, it has become fundamental in identifying critical variables and their clinical relevance in the development of new drugs. In process monitoring, it has been used to highlight in-line real-time analysis, and it has been used more commonly since 2004 when the Food and Drug Administration (FDA) launched Process Analytical Technology (PAT), integrated with the concepts of Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century. The present review presents advances in the application of this tool in the development of pharmaceutical products and processes in the last six years.

A derivative spectrophotometric method was validated for quantification of acyclovir in poly (n-butylcyanoacrylate) (PBCA) nanoparticles. Specificity, linearity, precision, accuracy, recovery, detection (LOD) and quantification (LOQ) limits were established for method validation. First-derivative at 295.2 nm eliminated interferences from nanoparticle ingredients and presented linearity for acyclovir concentrations ranging from 1.25 to 40.0 µg/mL (r = 0.9999). Precision and accuracy data demonstrated good reproducibility. Recovery ranged from 99.3 to 101.2. LOD was 0.08 µg/mL and LOQ, 0.25 µg/mL. Thus, the proposed method proved to be easy, low cost, and accurate, and therefore, an useful alternative to quantify acyclovir in nanoparticles.

Partially and fully perforated pan coaters are among the most relevant types of equipment currently used in the process of coating tablets. The goal of this study was to assess the performance differences among these types of equipment employing a factorial design. This statistical approach allowed the simultaneous study of the process variables and verification of interactions among them. The study included partially-perforated and fully-perforated pan coaters, aqueous and organic solvents, as well as hypromellose-based immediate-release coating. The dependent variables were process time, energy consumption, mean weight of tablets and process yield. For the tests, placebo tablets with a mean weight of 250 mg were produced, divided into eight lots of two kilograms each and coated in duplicate, using both partially perforated pan and fully perforated pan coaters. The results showed a significant difference between the type of equipment used (partially and fully perforated pan coaters) with regard to process time and energy consumption, whereas no significant difference was identified for mean weight of the coated tablets and process yield.Entre os tipos de equipamentos de maior relevância utilizados atualmente no processo de revestimento de comprimidos estão os de tambor parcial e totalmente perfurados. A proposta desse trabalho foi avaliar as diferenças de desempenho entre esses equipamentos empregando projeto fatorial. Essa abordagem estatística possibilitou o estudo simultâneo das variáveis do processo, permitindo verificar interações entre elas. O trabalho incluiu equipamento com tambor parcialmente perfurado e totalmente perfurado, solventes aquoso e orgânico, assim como revestimento de liberação imediata à base de hipromelose. As variáveis dependentes ou respostas foram tempo de processo, consumo de energia, peso médio e rendimento do processo. Para os ensaios, foram produzidos comprimidos de placebo de 250 mg de peso médio, divididos em 8 lotes de dois quilogramas cada e revestidos em duplicata, tanto no equipamento com tambor parcialmente perfurado quanto no equipamento de tambor totalmente perfurado, obedecendo a matriz de ensaio previamente definida. Os resultados mostraram que existe diferença significativa entre equipamento de tambor parcialmente perfurado e totalmente perfurado, para tempo de processo e consumo de energia. Já para peso médio dos comprimidos revestidos e rendimento do processo, os dois equipamentos não apresentaram diferença significativa.

Hydroxymethylnitrofurazone (NFOH) is a new compound with potential leishmanicidal and trypanocidal activity. Despite its effectiveness, the formulators have to overcome its poor aqueous solubility. Recently, polymeric nano-scale drug delivery systems have proposed for the treatment of neglected diseases. As several studies have confirmed the advantages of such formulations, and this approach provides new analytical challenges, including the need to detect trace amounts of the drug. A suitable method was developed and validated for NFOH determination bound to poly (n-butylcyanoacrylate) (PBCA) nanoparticles. The chromatographic separation was achieved using a C18 column maintained at 25 ºC and an isocratic mobile phase consisting of water and acetonitrile: 80:20 (v/v) at a flow rate of 1.2 mL min-1 and UV-detection at 265 nm. Investigated validation parameters included selectivity, linearity, accuracy, precision and robustness (changes in column temperature, mobile phase composition and flow). The method was specific, the peak of NFOH had no interference with any nanoparticle excipients and no co-elution with main degradation product (nitrofurazone). Linearity was over the range of 0.94 13.11 μg mL-1 (r2=0.999). The method was accurate and precise, recovery of 100.7%, RSD of 0.4%; intra-day and inter-day RSD range 9.98-9.99 μg mL-1 and 0.3% to 0.5%, respectively. Robustness confirmed that method could resist the applied changes. Application of the optimized method revealed an encapsulation efficiency of 64.4% (n=3). Therefore, the method was successfully developed and validated for the determination of the encapsulation efficiency of NFOH-PBCA nanoparticles.