Solid Drug Research Articles

Non-invasive, continuous oral delivery of solid levodopa-carbidopa for management of Parkinson's disease.

When short plasma half-life drugs act only briefly, they require frequent or continuous administration. We report the engineering of a non-invasive oral drug delivery system for long-term, continuous administration of these drugs. Their non-invasive, long-term, continuous administration at daily doses exceeding 100 mg has, for many years, been considered an insurmountable challenge. We show that over 1200 mg/day of 4:1 levodopa-carbidopa (LD-CD) can be non-invasively and continuously extruded when formulated as a semisolid paste, loaded with 63%w/w of the solid drugs. The drug delivery system comprises a reusable orthodontic retainer with a co-molded pocket into which the patient inserts after each meal a new 1 mL propellant-driven, prefilled, disposable, drug delivery extruder. The paste is delivered to the lingual side of the teeth where it is mixed with saliva and swallowed. As reported elsewhere, a 15-day, 16 patient open label clinical trial of the drug delivery system continuously extruding LD-CD paste significantly reduces the variability of the plasma LD concentration and alleviates symptoms of advanced Parkinson's disease (PD) as compared to LD-CD tablets.

Evaluating Various Lactose Types as Solid Carriers for Improving Curcumin Solubility in Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDSs) for Oral Administration

Curcumin, a bioactive compound derived from turmeric, possesses numerous pharmaceutical properties; however, its poor aqueous solubility and permeability result in low bioavailability. This study aims to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) using different lactose types as solid carriers for the oral administration of curcumin to enhance its solubility. The system comprised curcumin, an oil phase, and a surfactant. Jasmine oil, as the oil phase, and Cremophor® RH40, as the surfactant, were selected due to their superior ability to solubilize curcumin. A microemulsion was then prepared using a ternary phase diagram. The liquid SNEDDSs were converted into S-SNEDDSs by employing three solid carriers: Tablettose® 80, FlowLac® 100, and GranuLac® 200. Dissolution studies conducted in simulated gastric fluid demonstrated a significant improvement in curcumin solubility in the S-SNEDDS formulations compared to curcumin powder. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses confirmed the appearance of curcumin in the S-SNEDDS, while Fourier-transform infrared (FTIR) spectroscopy indicated compatibility between the excipients and curcumin. Additionally, an accelerated stability study conducted over four weeks at 40 °C and 75% relative humidity showed no significant changes in the physical appearance of the S-SNEDDS formulations. These findings suggest that the S-SNEDDS formulation effectively enhances curcumin’s solubility, potentially improving its bioavailability for oral administration.

Locally Acting Budesonide-Loaded Solid Self-Microemulsifying Drug Delivery Systems (SMEDDS) for Distal Ulcerative Colitis

Locally Acting Budesonide-Loaded Solid Self-Microemulsifying Drug Delivery Systems (SMEDDS) for Distal Ulcerative Colitis

Development of a novel apixaban-loaded solid self-emulsifying drug delivery system for oral administration: physicochemical characterization and pharmacokinetics in rats

Development of a novel apixaban-loaded solid self-emulsifying drug delivery system for oral administration: physicochemical characterization and pharmacokinetics in rats

The role of coatings and plasticizers compatibility in stability of advanced gastro-resistant self-emulsifying pellets designed for the delivery of volatile compounds: A combined solid-state NMR and dissolution study

The gastro-resistant behaviour of solid self-emulsifying drug delivery systems (S-SEDDS) represents a significant and innovative advancement in delivering poorly soluble drugs. Due to the complexity of these systems and the liquid nature of SEDDS, thorough investigation is essential. This study explored the stability of self-emulsifying (SE) pellets containing the volatile compound thymol coated with gastro-resistant Eudragit® L 30 D-55 water dispersion. The SE pellet cores, composed of Neusilin® US2 with adsorbed SEDDS (thymol, triacylglycerol, Labrasol®, and propylene glycol), microcrystalline cellulose, and chitosan, were prepared using the extrusion/spheronization method and demonstrated optimal technological properties. The 6-month stability of three coating compositions, differing in thickness and triethyl citrate (TEC) concentration in the Eudragit® L topcoat, or the application of an ethylcellulose (EC, Surelease®) sub-coat, was investigated using the combined in vitro dissolution testing and solid-state nuclear magnetic resonance (ss-NMR) for detailed structural characterization. The dissolution data of samples with Eudragit® L topcoat data showed an acceleration of thymol release in acidic conditions, preventing the SE pellets from achieving gastro-resistance. The ss-NMR analysis revealed an incompatibility between TEC and SEDDS (specifically propylene glycol), identified as a TEC phase transition to a liquid phase independent of TEC concentration. Additionally, ss-NMR analysis revealed that neat thymol negatively affected coating layer stability by promoting the plasticization of Eudragit® L. The inclusion of a 10 % Surelease® sub-coat yielded positive results, maintaining the gastro-resistant properties of SE pellets stored under 25 °C/60 % RH for 6 months. However, ss-NMR analysis confirmed ongoing TEC liquefaction after 3 and 6 months, indicating that the oleic acid and triglycerides in Surelease® as plasticizers contributed to this instability. Therefore, this formulation cannot be deemed stable, and using Surelease® as a sub-layer is only a temporary solution. Overall, while plasticizers are commonly used in pharmaceutical technology, they can introduce significant problems in S-SEDDS development, and their use in sub- or topcoats should be carefully considered or avoided. At the same time, it became evident that in-vitro dissolution testing alone cannot capture the slow processes and interactions occurring within the internal structure of these systems.

Mechanistic Model for Drug Release from PLGA-Based Biodegradable Implants for In Vitro Release Testing: Development and Validation.

Several factors can affect drug release from polylactide coglycolide (PLGA)-based formulations, including polymer and drug properties, formulation components, manufacturing processes, and environmental in vitro or in vivo conditions. To achieve optimal release profiles for specific drug delivery applications, it is crucial to understand the mechanistic processes that determine drug release from PLGA-based formulations. In the current study, we developed a mechanistic model for the in vitro drug release of PLGA-based solid implants. The model accounts for all known critical quality attributes (CQAs) and considers the most important release rate processes, including water or dissolution medium influx into the porous structure of the implant, initial noncatalytic hydrolysis of PLGA, autocatalytic hydrolysis, dissolution of oligomers and monomers into the aqueous medium, the liberation of the trapped solid drug from the polymer matrix, dissolution of the solid drug into the wetted pore network, diffusion of the dissolved drug out of the implant, and distribution of the dissolved drug into the dissolution medium. The model has been validated using in vitro release data obtained from implants of four drugs (buserelin, afamelanotide, brimonidine, and nafarelin). The model presented in this manuscript provides valuable insights into the kinetics and mechanism of drug release from PLGA-based solid implants and has demonstrated the potential for optimizing formulation design. The in vitro release model, coupled with physiologically based pharmacokinetic (PBPK) modeling, can predict the in vivo performance of implants and can be used to support bioequivalence studies in a drug development program.

The Key Role of Wettability and Boundary Layer in Dissolution Rate Test.

The present work proposes a mathematical model able to describe the dissolution of poly-disperse drug spherical particles in a solution (Dissolution Rate Test-DRT). DRT is a pivotal test performed in the pharmaceutical field to qualitatively assess drug bioavailability. The proposed mathematical model relies on the key hallmarks of DRT, such as particle size distribution, solubility, wettability, hydrodynamic conditions in the dissolving liquid of finite dimensions, and possible re-crystallization during the dissolution process. The spherical shape of the drug particles was the only cue simplification applied. Two model drugs were considered to check model robustness: theophylline (both soluble and wettable) and praziquantel (both poorly soluble and wettable). The DRT data analysis within the proposed model allows us to understand that for theophylline, the main resistance to dissolution is due to the boundary layer surrounding drug particles, whereas wettability plays a negligible role. Conversely, the effect of low wettability cannot be neglected for praziquantel. These results are validated by the determination of drug wettability performed while measuring the solid-liquid contact angle on four liquids with decreasing polarities. Moreover, the percentage of drug polarity was determined. The proposed mathematical model confirms the importance of the different physical phenomena leading the dissolution of poly-disperse solid drug particles in a solution. Although a comprehensive mathematical model was proposed and applied, the DRT data of theophylline and praziquantel was successfully fitted by means of just two fitting parameters.

Investigation of Rheological Properties of Molten Materials for Dripping Pills Based on Imaging Monitoring.

Rheological properties, as critical material attributes (CMAs) of solid dispersion drugs such as dripping pills, affect the melting, dispersion, and solidification. Therefore, characterization and assessments of rheological properties in the pharmaceutical process are important in enhancing drug stability and bioavailability. The study aimed to develop a method for analyzing the rheology of molten materials, assessing their consistency and how rheological properties affect the dripping process and pills quality. The rheological behavior of molten materials composed of Ginkgo biloba leaf extract (GBE) and polyethylene glycol (PEG) 4000 was characterized. Batch consistency of molten materials was evaluated. Image monitoring technology was utilized to capture and process images of the droplet formation process. We established the relationship between the rheological properties of molten materials and various attributes. The quality consistency of molten materials was evaluated, with 12 batches showing similarity above 0.8. The MLR models showed strong correlations (R2 > 0.80) between rheological properties and evaluation attributes. The rheological properties, including consistency coefficient, flow index, and viscosity at 80°C, were identified as critical rheological properties of the molten materials. Rheological property differences of molten materials have an impact on the morphology of droplet and quality performance. A rheological method was established, enabling quality consistency evaluation of molten materials in dripping pills. This study revealed the influence of rheological properties on droplet formation process and dripping pills quality, providing a reference for researches on material attributes control of other traditional Chinese medicine dripping pills.

Mass balance analysis for therapeutic peptides: Case studies, applications, and perspectives

The concept of mass balance is discussed as it pertains to the pharmaceutical development of therapeutic peptides. Case studies are presented demonstrating how to perform a mass balance assessment on solid drug substance and solution drug product, and the role of mass balance in the context of the overall product control strategy is discussed. Utilizing mass balance as a specification test where the result is calculated from other critical quality attribute tests, each with their own specification, offers little value as a formalized quality acceptance criterion and may create more deviations, non-value added investigations, and potential batch failures. While useful in characterizing the performance of analytical methods and as part of a rigorous understanding of the manufacturing process and control strategy development, mass balance should not be required as a specification control and should instead be demonstrated during method development and through well-designed forced degradation experiments. Analytical method variability is discussed in relation to the analytical target profile, and the overall impact of sources of variability on the mass balance calculation is described in support of this position.

Enhanced Anti-Inflammatory Activity of Kaempferia galanga Extract by Solid Self-Nanoemulsifying Drug Delivery System and Its Development in Fast Disintegrating Tablet

The increasing global incidence of osteoarthritis (OA) emphasizes the need for effective treatments, particularly for the elderly. Conventional OA treatments pose administration challenges, leading to patient discomfort due to difficulties in administration. Herbal formulations offer an alternative to mitigate these issues. Kaempferia galanga (KG) contains ethyl p-methoxycinnamate, a compound displaying anti-inflammatory properties that hold promise for OA treatment. This study explores the formulation of a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of Kaempferia galanga extract (KGE) and evaluates its anti inflammatory efficacy, subsequently developing it into a fast disintegrating tablet (FDT) dosage form. Initially, a liquid SNEDDS (L-SNEDDS) was prepared with varying surfactant and co surfactant concentrations. The optimal formula of L-SNEDDS (FL2) using tween 80: cremophor RH 40: PEG 400 in a ratio of 1:1:2 demonstrated favorable characteristics, including transmittance of 86.93 ± 1.16%, emulsification time of 28 ± 2.65 s, particle size of 27.79 ± 2.00 nm, PDI of 0.21 ± 0.014, and zeta potential of -12.57 mV. FL2 was solidified using aerosil 200 to produce S-SNEDDS and tested for anti-inflammatory efficacy in vivo using a carrageenan induced rat model. Results showed enhanced anti-inflammatory efficacy of KGE via S-SNEDDS, marked by reduced edema volume. Afterward, FDT S-SNEDDS were prepared using the direct compression method by comparing different types of superdisintegrants. The formulation using the combination of crospovidone and croscarmellose sodium (FT2) demonstrated excellent flow properties, tablet disintegration time of 63 s, wetting time of 34.01 ± 7.87 s, friability of 0.19%, and hardness of 3.53 ± 6.16 kg/cm2. The dissolution test indicated a better dissolution profile for FT2 compared to other formulations. In conclusion, this research presents the potential of FDT S-SNEDDS as a promising drug delivery system for enhancing the therapeutic effects of Kaempferia galanga extract in treating inflammatory conditions such as osteoarthritis.

Implications of crystal disorder on the solid-state stability of Olanzapine

Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.

Comparing Low-Dose Carvedilol Continuous Manufacturing by Solid and Liquid Feeding in Self-Emulsifying Delivery Systems via Hot Melt EXtrusion (SEDEX)

Background/Objectives: This study compared two pilot scale continuous manufacturing methods of solid self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME). Methods: A model poorly water-soluble drug carvedilol in low dose (0.5–1.0% w/w) was processed in HME either in a conventional powder form or pre-dissolved in the liquid SEDDS. Results: HME yielded a processable final product with up to 20% w/w SEDDS. Addition of carvedilol powder resulted in a non-homogeneous drug distribution in the extrudates, whereas a homogeneous drug distribution was observed in pre-dissolved carvedilol. SEDDSs were shown to have a plasticizing effect, reducing the HME process torque up to 50%. Compatibility between excipients and carvedilol in the studied ratios after HME was confirmed via DSC and WAXS, demonstrating their amorphous form. Solid SEDDSs with Kollidon® VA64 self-emulsified in aqueous medium within 15 min with mean droplet sizes 150–200 nm and were independent of the medium temperature, whereas reconstitution of Soluplus® took over 60 min and mean droplet size increased 2-fold from 70 nm to 150 nm after temperature increased from 25 °C to 37 °C, indicating emulsion phase inversion at cloud point. Conclusions: In conclusion, using Kollidon® VA64 and pre-dissolved carvedilol in SEDDS has shown to yield a stabile HME process with a homogenous carvedilol content in the extrudate.

Development and Characterization of Olaparib-Loaded Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Pharmaceutical Applications.

This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25℃) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.

Solid Self Nano-Emulsifying Drug Delivery System of Dasatinib: Optimization, In-vitro, Ex-vivo and In-vivo assessment.

Aim: Dasatinib (DST) is an oral tyrosine kinase inhibitor with poor aqueous solubility. To outwit this issue, a solid self-nano emulsifying drug delivery system (S-SNEDDS) of DST was formulated.Methods: I-optimal mixture design was used for optimization of DST-loaded SNEDDS using Linalool, Cremophor RH40 and Transcutol P. S-SNEDDS underwent physicochemical characterization, in-vitro release and ex-vivo permeation, cell-based assays and pharmacokinetic study.Results: DST-S-SNEDDS showed globule size and PDI of 141.53±5.371nm and 0.282±0.020, respectively. DST-S-SNEDDS revealed significantly lower IC50 (1.825μg/mL) than free DST (7.298μg/mL) in MDA-MB-231. In-vivo pharmacokinetic study revealed 1.94-fold increment in AUC0-t for the DST-S-SNEDDS group than free DST.Conclusion: S-SNEDDS could be promising approach for improving bioavailability and efficacy of DST.

Determination of bioequivalence between generic and reference drugs using laser-induced breakdown spectroscopy

BackgroundIn vitro bioequivalence studies are strictly limited to the comparison of dissolution performance to a reference drug. These studies are performed without considering the chemical similarity between the generic and reference drug formulations. This work has focused on developing a groundbreaking method based on the laser-induced breakdown spectroscopy (LIBS) technique for the in vitro bioequivalence determination of immediate-release solid oral dosage form generic drugs and as an alternative method for establishing the biowaiver of in vivo generic drug studies. ResultsThe novel LIBS-based methodology to determine in vitro bioequivalence is fast, easy to perform, and can be carried out without the requirement of tedious and complicated sample pre-treatment, nor expensive instrumentals and reagents, almost directly on the drug samples. Furthermore, the proposed methodology demonstrated that it is enough to identify the spectrochemical similarity of the formulation between generic drugs to a reference drug through the chemometric study of their LIBS spectra, based on the determination of the differentiation and similarity factors, f1 and f2, respectively, used in the pharmaceutical industry in this purpose. After analysing their LIBS spectra, the generic drugs selected for this work have all been shown to be in vitro bioequivalent, given their f1 values of less than 15 and f2 values greater than 50, according to the technical regulations on which the American and European medicines agencies are based for the approval of registration for generic immediate-release solid oral dosage form drugs. This has been evidenced even for drugs from Class III and Class IV of the biopharmaceutical classification system, whose active principle nominal concentration is very low as 0.1 and 0.25 mg/tablet, respectively. Significancefor the first time the LIBS technique has been successfully used in an advanced application for the pharmaceutical industry. The proposed method constitutes a reliable and specialized methodology for the establishment of formulation similarity between two drugs, without the requirement of separate identification of each of their components, which is a new and potential tool to determine the in vitro bioequivalence for generic immediate-release solid oral dosage form drugs.

640P Tumor response rate for hematologic and solid cancer drugs with FDA approval supported by single-arm trials

640P Tumor response rate for hematologic and solid cancer drugs with FDA approval supported by single-arm trials

Advances in Nanoemulsion Formulations for Enhanced Drug Delivery: A Comprehensive Review

Abstract: Nanoemulsions (NEs) have emerged as adaptable medication delivery methods with extensive applications in both pharmaceuticals and cosmeceuticals. This comprehensive review delves into the myriad advantages of NEs, ranging from enhanced drug absorption to providing stability for chemically unstable compounds. NEs exhibit promising potential as substitutes for liposomes, offering improved performance in various formulations. In the realm of cosmeceuticals, NEs play a pivotal role in enabling rapid skin penetration while maintaining skin moisturization, thanks to their visually appealing coating. Their ability to deliver active ingredients efficiently makes them an attractive option for cosmetic formulations seeking enhanced efficacy. Moreover, this review sheds light on the involvement of NEs in antimicrobial therapies and gene therapy, underscoring their versatility and potential in addressing diverse medical challenges. Additionally, NEs find applications in commercial disinfectants, further highlighting their broad utility beyond traditional drug delivery systems. Furthermore, the review discusses innovative strategies, such as solid self-nanoemulsifying drug delivery systems (S-SNEDDS), which offer advantages in terms of stability, drug loading capacity, and patient compliance. By exploring these strategies, researchers aim to overcome existing limitations and optimize the therapeutic potential of NEs.

Optimization of solid dispersion technique and gliclazide to carrier (PVP K30) ratio for solubility enhancement

Background and objective: Poorly water-soluble dugs provide less dissolution rate and bioavailability; hence, it minimizes the pharmacological effect of orally administered medications. Gliclazide is a sulfonylurea antidiabetic medication of the second generation, used to treat type II diabetes mellitus. It belongs to the class II drugs of biopharmaceutic classification system, indicating that it has high permeability and poor aqueous solubility. The aim of this study is to determine an optimum solid dispersion method and drug to carrier ratio to improve the solubility of gliclazide. Methods: Solid dispersions of gliclazide were formulated with polyvinyl pyrrolidone K30 using various drug to carrier ratios (1:1, 1:3, and 1:5) by utilizing kneading and solvent evaporation methods. Solubility and dissolution rate of solid dispersion formulas were compared with pure drug and co-ground mixtures. The formulations were further evaluated in terms of percentage of yield, drug content, FTIR, SEM, DSC, and XRD studies. Results: The highest solubility improvement of gliclazide was obtained at the ratio 1:5 of gliclazide and PVP K30 utilizing solvent evaporation method, solubility increased about 2.54 folds (98.299 ± 5.77 µg/ml) as compared to pure gliclazide (38.739 µg/ml). Meanwhile, the greatest improvement in gliclazide dissolution rate was observed in the same solid dispersion formula that was about 105.76 % after 30 minutes. FTIR demonstrated no unwanted interaction between the drug and carrier. While, SEM, DSC, and XRD showed crystallinity of the drug was minimized and converted to amorphous form in solid dispersion formula. Conclusion: Based on the investigations of this study, it can be concluded that the drug to carrier weight ratios and preparation methods had the influence on the drug solubility and the release rate. The obtained data revealed that the solvent evaporation is the best method of solid dispersion for enhancing gliclazide solubility using PVP K30 with the ratio 1:5 of the drug and carrier.

Biosurfactants as stabilizers of niclosamide nanocrystals: Enhancing stability, solubility, and cytotoxicity profiling

Biosurfactants are surface-active compounds of biological origin, stable over a wide range of temperature, pH, and salinity. In this work, the ability of the biosurfactants rhamnolipid (RAM), sophorolipid (SOFO) and surfactin (SURF) to stabilize a nanocrystal suspension of niclosamide (NCL) in water, and to enhance the drug solubility were evaluated. The performances were compared with those of the synthetic surfactants tween 80 (TW) and soluplus (SOLU). Overall, RAM, SOFO, and SURF proved to be as effective as TW and SOFO in terms of NCL nanocrystal suspension stabilization. Formulations containing 3 % (w/w) surfactant exhibited the best stability at 4 °C and 25 °C. The three biosurfactants also led to an improvement of aqueous NCL solubility, even when a slurry of the micronized drug was used without nanocrystal formulation. The best performance was observed for the SURF 3 % (w/w) nanocrystal formulation (1157.48 μg/mL), which released more than twice the amount of NCL compared to the best synthetic surfactant formulation (TW 3 % (w/w), 542.57 μg/mL), and 622 times more than the pure solid drug (1.86 μg/mL). Cell viability was not compromised by the surfactants alone, indicating that the formulation cytotoxic effect is related to the enhanced solubilization of NCL. Consistently, the NCL/SURF formulation was the most effective, achieving a maximum cytotoxicity effect of 80 % at a concentration of 1000 nM, while the other formulations reached a maximum effect of 71 % at concentrations starting from 1500 nM. Nevertheless, when the balance between formulation stability, drug release enhancement, and cytotoxicity is considered the three biosurfactants studied in this work showed significant potential advantages relative to synthetic analogues that can be explored in pharmaceutical development.

Prediction of Degradation Profiles for Various Sartans under Solvent-Free Mechanochemical Conditions.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.