Development of bedaquiline nanoemulsions intended for paediatric multidrug-resistant tuberculosis: excipient selection and preformulation studies.

Preformulation investigations into the development of drug formulations, encompassing considerations related to the structure of the drug, excipients, composition, and physical attributes are crucial. This phase is pivotal in ensuring the ultimate success of nanoemulsion development. The objective of this study was to evaluate and define the properties of bedaquiline (BDQ) and the necessary excipients for the formulation of self-emulsifying BDQ-loaded nanoemulsions. To determine the saturation solubility of BDQ in various oils, an in-house validated HPLC method was used. Fourier transform infrared spectroscopy was utilised to identify and evaluate the compatibility between BDQ and the selected excipients. The water titration method was used to construct phase diagrams to identify the type of structure that resulted following emulsification and to characterise the behaviour of mixtures along dilution paths. The solubility studies revealed that BDQ exhibited the highest solubility in olive oil, with a solubility of 3.45 ± 0.041 mg/ml. The design space led to the formation of emulsions categorised as Winsor products. Importantly, the FTIR data indicated the absence of any potential interactions between BDQ and the chosen excipients. The preformulation studies were successful and facilitated the selection of compatible and suitable excipients for the formulation of BDQ-loaded nanoemulsions.

A comprehensive assessment of machine learning algorithms for enhanced characterization and prediction in orodispersible film development.

Orodispersible films (ODFs) have emerged as innovative pharmaceutical dosage forms, offering patient-specific treatment through adjustable dosing and the combination of diverse active ingredients. This expanding field generates vast datasets, requiring advanced analytical techniques for deeper understanding of data itself. Machine learning is becoming an important tool in the rapidly changing field of pharmaceutical research, particularly in drug preformulation studies. This work aims to explore into the application of machine learning methods for the analysis of experimental data obtained by ODF characterization in order to obtain an insight into the factors governing ODF performance and use it as guidance in pharmaceutical development. Using a dataset derived from extensive experimental studies, various machine learning algorithms were employed to cluster and predict critical properties of ODFs. Our results demonstrate that machine learning models, including Support vector machine, Random forest and Deep learning, exhibit high accuracy in predicting the mechanical properties of ODFs, such as flexibility and rigidity. The predictive models offered insights into the complex interaction of formulation variables. This research is a pilot study that highlights the potential of machine learning as a transformative approach in the pharmaceutical field, paving the way for more efficient and informed drug development processes.

The challenge of downstream processing of spray dried amorphous solid dispersions into minitablets designed for the paediatric population - A sustainable product development approach.

Poorly water-soluble drugs present a significant challenge in the development of oral solid dosage forms (OSDs). In formulation development the appropriate use of excipients to adjust solubility, and the choice of manufacturing method and pharmaceutical processes to obtain a dosage form to meet the needs of the patient group, is crucial. Preparing an amorphous solid dispersion (ASD) is a well-established method for solubility enhancement, and spray drying (SD) a common manufacturing method. However, the poor flowability of spray dried materials poses a significant challenge for downstream processing. Promoting sustainability in OSD development involves embracing a versatile formulation design, which enables a broader spectrum of patients to use the product, as opposed to altering existing dosage forms retrospectively. The objective of the current study was to develop a formulation of spray dried indomethacin ASD suited to the production, by direct compression, of instant release paediatric minitablets. Excipients evaluated were PVP or HPMCAS in solid dispersions at the preformulation phase, and MCC and lactose as a filler in direct compression. From the studied formulations, a 3:1 ratio blend of Vivapur 200/Pharmatose 200 M (MCC/lactose) with 0.5% (w/w) magnesium stearate was found to be the most promising in tableting, and minitablets containing a 6.22% content of spray-dried ASD of indomethacin/PVP K 29-32 could be obtained with desired tablet hardness and pharmaceutical quality, complying with tests of weight variation and fast disintegration in an aqueous environment. As a case example, this study provides a good foundation for further studies in harnessing a sustainable approach to the development of pharmaceutical formulations that can appropriately serve different patient sub-populations.

W/O/W Microemulsions for Nasal Delivery of Hydrophilic Compounds: A Preliminary Study.

The administration of hydrophilic therapeutics has always been a great challenge because of their low bioavailability after administration. For this purpose, W/O/W microemulsion resulted to be a potential successful strategy for the delivery of hydrophilic compounds, interesting for the nasal mucosal therapy. Herein, an optimized biphasic W/O microemulsion was designed, through a preliminary screening, and it was inverted in a triphasic W/O/W microemulsion, intended for the nasal administration. In order to enhance the mucosal retention, surface modification of the biphasic W/O microemulsion was performed adding didodecyldimethylammonium bromide, and then converting the system into a cationic triphasic W/O/W microemulsion. The developed samples were characterized in terms of droplet size, polydispersity, zeta potential, pH and osmolality. The physical long-term stability was analyzed storing samples at accelerated conditions (40 ± 2 °C and 75 ± 5 % RH) for 6 months in a constant climate chamber, following ICH guidelines Q1A (R2). In order to verify the potential retention on the nasal mucosa, the two triphasic systems were analyzed in terms of mucoadhesive properties, measuring the in vitro interaction with mucin over time. Furthermore, fluorescein sodium salt was selected as a model hydrophilic drug to be encapsulated into the inner core of the two triphasic W/O/W microemulsions, and its release was analyzed compared to the free probe solution. The cytocompatibility of the two platforms was assessed on two cell lines, human fibroblasts HFF1 and Calu-3 cell lines, chosen as pre-clinical models for nasal and bronchial/tracheal airway epithelium.

Solid-State Phase Transformation of Monohydrate and Anhydrous Form II of Sitagliptin Phosphate into a Novel Anhydrous Form IV - Solvent-Driven, Temperature-Induced and Stress Testings.

The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time.

Potential of pharmaceutical formulation based on Morinda citrifolia extract for the treatment of schistosomiasis.

Schistosomiasis is a parasitic disease that can be asymptomatic, but it can progress and cause serious damage, such as hospitalization and death. This work aimed to characterize and carry out the in vivo pharmacological test of the dry extract of Morinda citrifolia and obtain a pharmaceutical dosage form based on this extract for the treatment of schistosomiasis. The aqueous extract was characterized based on the evaluation of pH, dry residue and density. The aqueous extract was dried through the freeze-drying process. The obtained dry extract was characterized through phytochemical screening, rheological analysis, acute toxicity and in vivo pharmacology. Additionally, the pre-formulation development of a pharmaceutical dosage form was pursued with the dry extract. Through the HPLC chromatogram, characteristic rutin peaks were identified. The rheological behavior of the dry extract did not show good characteristics. Acute toxicity, at a dose of 2000 mg/kg, showed excitatory activity in the central and autonomous nervous system. The in vivo pharmacological test of the dry extract showed that, at a dose of 400 mg/kg, it was possible to reduce 67.5% of the total adult worms, 66% of female worms and 60% of the number of eggs. The pharmaceutical dosage form obtained was an oral solution that was clear, transparent, without the presence of lumps and precipitates, having a density of 1.1276 g mL-1 and pH of 5.92. The results obtained will provide parameters for the production of suitable pharmaceutical formulations, as well as for the quality control of products based on M. citrifolia, with promising schistosomicidal activity.

Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in Solution.

Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C-H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol-1 when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201's sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act.

Preformulation-Assisted Design of Ketorolac Tromethamine for Effective Ophthalmic Delivery.

Background: The eye is a highly protected organ from ocularly administered drugs; drug- and formulation-related factors contribute significantly to ocular bioavailability. There has been a growing interest in using nonsteroidal anti-inflammatory drugs in ophthalmology for treating postoperative pain, inflammation, and seasonal allergic conjunctivitis. A preformulation-assisted design boosts efficacy and reduces dose requirements. Methods: This work aims to study the preformulation characteristics of ketorolac tromethamine to improve ocular performance and future formulation development through developing an high-performance liquid chromatography (HPLC) stability-indicating assay, forced degradation under stress conditions, solubility, as well as partition and distribution coefficient measurements. An isocratic HPLC with diode array detector method was developed and validated. Accelerated degradation under different stressors (acid, alkali, heat, and oxidative) was studied. In addition, solubility, partition, and distribution were investigated at different pHs of 3.5-7.4. Results: The results indicated that the developed HPLC method was simple, rapid (retention time ≃3 min), sensitive, selective, robust, and stability indicating. The drug seems more chemically sensitive to acid degradation (∼30% and 40% of the drug was degraded under 0.1 M and 1 M HCl at 60°C for 24 h, respectively). Another significant degradation was recorded in the following order: Oxidative > alkali > heat (phosphate-buffered saline) > heat (distilled water). Being a weak ionizable drug, both water and lipid solubility, as measured through partition coefficients, it demonstrated pH-dependency. Conclusion: For the optimum balance of water and lipid solubility required for penetration through the lipophilic corneal epithelial barrier, ketorolac eye drops would be better formulated between pH 5.5 and 6.6 than being formulated at the physiological fluid pH 7.4, where the drug is extremely hydrophilic and less permeable.

Insights into the formulation properties, biocompatibility, and permeability of poorly water-soluble methoxyflavones with PEG400 and propylene glycol.

Herein, thermal and non-thermal techniques were used to elucidate the putative physical and chemical interactions between poorly water-soluble Kaempferia methoxyflavones and PEG400/propylene glycol. Additionally, the biocompatibility of methoxyflavone-glycol solutions was evaluated using Caco-2 cells whereas the absorptive transport was investigated by measuring the apparent permeability coefficient (P app) of the methoxyflavones and transepithelial electrical resistance (TEER) of the Caco-2 cell monolayer. Data from differential scanning calorimetry, Fourier-transform infrared (FTIR), and proton nuclear magnetic resonance (1H NMR) spectroscopic analysis revealed physico-chemical compatibility between the three methoxyflavones and PEG400/propylene glycol. Furthermore, PEG400 and propylene glycol solutions of the methoxyflavones were shown to be compatible with Caco-2 cells at pharmacologically effective concentrations. In vitro transport studies across the Caco-2 cell monolayer revealed high P app values of 24.07 × 10-6 to 19.63 × 10-6 cm s-1 for PEG400 solutions of the methoxyflavones. The TEER values of the Caco-2 cell monolayers indicated that the increased drug transport was partly due to increased tight junction openings, but without compromising the epithelial barrier integrity. The good pharmaceutical and biocompatibility profiles, as well as improved transport of the methoxyflavones in PEG400 and propylene glycol solutions, are suggestive of the worthiness of this approach for further consideration pertaining to the development of these drugs into oral liquid dosage forms.

SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening.

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source.

A robust, viable, and resource sparing HPLC-based logP method applied to common drugs.

Reliable, experimentally determined partition coefficient P (logP) for most drugs are often unavailable in the literature. Many values are from in silico predictions and may not accurately reflect drug lipophilicity. In this study, a robust, viable, and resource sparing method to measure logP was developed using reverse phase high performance liquid chromatography (RP-HPLC). The logP of twelve common drugs was measured using calibration curves at pH 6 and 9 that were created using reference standards with well-established logP. The HPLC method reported here can be used for high throughput estimation of logP of commonly used drugs. LogP values here showed general agreement with the other few HPLC-based literature logP values available. Additionally, the HPLC-based logP values found here agreed partially with literature logP values found using other methodologies (±10%). However, there was no strong agreement since there are few experimentally determined literature logP values. This paper shows a facile method to estimate logP without using octanol or computational approaches. This method has excellent promise to provide reliable logP values of commonly used drugs available in literature. A larger pool of reliable logP values of commonly drugs has promise to improve quality of medicinal chemistry and pharmacokinetic (PK) models.

Rational Design of Topical Semi-Solid Dosage Forms-How Far Are We?

Specific aspects of semi-solid dosage forms for topical application include the nature of the barrier to be overcome, aspects of susceptibility to physical and chemical instability, and a greater influence of sensory perception. Advances in understanding the driving forces of skin penetration as well as the design principles and inner structure of formulations, provide a good basis for the more rational design of such dosage forms, which still often follow more traditional design approaches. This review analyses the opportunities and constraints of rational formulation design approaches in the industrial development of new topical drugs. As the selection of drug candidates with favorable physicochemical properties increases the speed and probability of success, models for drug selection based on theoretical and experimental approaches are discussed. This paper reviews how progress in the scientific understanding of mechanisms and vehicle-influence of skin penetration can be used for rational formulation design. The characterization of semi-solid formulations is discussed with a special focus on modern rheological approaches and analytical methods for investigating and optimizing the chemical stability of active ingredients in consideration of applicable guidelines. In conclusion, the combination of a good understanding of scientific principles combined with early consideration of regulatory requirements for product quality are enablers for the successful development of innovative and robust semi-solid formulations for topical application.

Dataset development of pre-formulation tests on fast disintegrating tablets (FDT): data aggregation.

OBJECTIVES: Tablet manufacturing development is costly, laborious, and time-consuming. Technologies related to artificial intelligence like ,predictive model ,can be used in the control process to facilitate and accelerate the tablet manufacturing process. predictive models have become popular recently. However, predictive models need a comprehensive dataset of related data in the field, due to the lack of a dataset of tablet formulations, the aim of this study is to aggregate and integrate fast disintegration tablet's formulation into a comprehensive dataset. DATA DESCRIPTION: The search strategy has been prepared between the years of 2010 to 2020, consisting of the keyword's 'formulation' ,'disintegrating' and 'Tablet', as well as their synonyms. By searching four databases, 1503 articles were retrieved, from these articles only 232 articles met all of the study's criteria. By reviewing 232 articles, 1982 formulations have been extracted, afterward pre-processing and cleaning data, contain steps of unifying the name and units, removing inappropriate formulations by an expert, and finally, data tidying was done on data. The developed dataset contains valuable information from various FDT's formulations, which can be used in pharmaceutical studies that are critical to the discovery and development of new drugs. this method can be applied to aggregate datasets from the other dosage forms.

Precellys® Evolution Homogenizer - a versatile instrument for milling, mixing, and amorphization of drugs in preformulation.

The aim of this work was the evaluation and introduction of the Bertin Precellys® Evolution homogenizer with Cryolys® as a valuable and versatile tool for the improvement of workflows in the preformulation phase of drug development. The presented pilot experiments indicate that the instrument can be applied for (1) screening of appropriate vehicles for the generation of micro- and nano suspensions, (2) small-scale manufacturing of suspension formulations for preclinical animal studies, (3) drug amorphization and identification of appropriate excipients for amorphous systems, and (4) preparation of homogenous powder blends. The instrument allows the rapid, parallel, and compound-sparing screening of formulation approaches and small-scale formulation manufacturing, in particular for low solubility compounds. For the characterization of generated formulations, miniaturized methods are introduced such as a screening tool for suspension sedimentation and redispersion and a non-sink dissolution model in biorelevant media in microtiter plates. This work summarizes exploratory, proof-of-concept studies and opens up new opportunities for more extended studies with this instrument in various application areas.

Predictive Nature of High-Throughput Assays in ADC Formulation Screening.

Utilization of high-throughput biophysical screening techniques during early screening studies is warranted due to the limited amount of material and large number of samples. But the predictability of the data to longer-term storage stability is critical as the high-throughput methods assist in defining the design space for the longer-term studies. In this study, the biophysical properties of two ADCs in 16 formulation conditions were evaluated using high-throughput techniques. Conformational stability and colloidal stability were evaluated by determining Tm values, kD, B22, and Tagg. In addition, the samples were placed on stability and the extent of aggregate formation over the 8-week interval was determined. The rank order of the 16 different formulations in the high-throughput assays was compared to the rank order observed during the stability studies to assess the predictive capabilities of the screening methods. It was demonstrated that similar rank orders can be expected between high-throughput physical stability indicating assays such as Tagg and B22 and traditional aggregation by SEC data, whereas conformational stability read-outs (Tm) are less predictive. In addition, the high-throughput assays appropriately identified the poor performing formulation conditions, which is ultimately what is desired of screening assays.

Pharmacokinetic evaluation of poorly soluble compounds formulated as nano- or microcrystals after intraperitoneal injection to mice.

Intraperitonial (i.p.) delivery during initial stages of drug discovery can allow efficacy readouts for compounds which have suboptimal pharmacokinetics (PK) due to poor physiochemical properties and/or oral bioavailability. A major limitation for widespread use of i.p. administration is the paucity of published data and unclear mechanisms of absorption, particularly when using complex formulations. The aim of the present study was to investigate the PK of poorly soluble compounds with low oral bioavailability when administered i.p. as crystalline nano- and microsuspensions. Three compounds, with varying aqueous solubility (2, 7, and 38 µM, at 37 °C), were dosed to mice at 10 and 50 mg/kg. In vitro dissolution confirmed that nanocrystals dissolved faster than microcrystals and hence were expected to result in higher exposure after i.p. dosing. Surprisingly, the increase in dissolution rate with decrease in particle size did not result in higher in vivo exposure. In contrast, the microcrystals showed higher exposure. The potential of smaller particles to promote access to the lymphatic system is hypothesized and discussed as one plausible explanation. The present work demonstrates the importance of understanding physicochemical properties of drug formulations in the context of the microphysiology at the delivery site and how that knowledge can be leveraged to alter systemic PK.

Characterization of piroctone olamine for topical delivery to the skin.

OBJECTIVE: Dandruff and its more severe related condition, seborrheic dermatitis affects a high proportion of the population at some point in their life. Piroctone olamine, also known as Octopirox® (OPX) is the monoethanolamine salt of piroctone and is an antifungal agent widely used for the management of dandruff. The aim of the present work was to characterize the physicochemical properties of piroctone olamine and to conduct pre-formulation studies for the development of novel topical formulations of this active. METHODS: An HPLC method was developed and validated for the analysis of OPX. The melting point was determined using the DSC Q2000 (TA Instruments, USA). The distribution coefficient (logD(O/PBS) ) and partition coefficient (log Po/w ) was determined in phosphate-buffered saline (PBS) AND deionized (DI) water using the shake flask method. All experiments were performed at room temperature. The solubility was determined experimentally by adding amount of active to a solvent. The samples were kept at 32° ± 1°C for 48 h in a water bath. The stability of the compound was determined in a range of solvents by preparing solutions of 1 mg mL-1 in the relevant solvents. These solutions were kept and stirred throughout the experiment at 32 ± 1°C, and aliquots were taken at 24, 48 and 96 h. RESULTS: The HPLC method was developed successfully; however, samples at the lower end of the calibration curve showed lower degrees of precision and accuracy. Based on experiments with DSC, the melting point was observed at an onset temperature of 132.4°C. The LogD was determined to be 1.84. The compound had the highest solubility in methanol (278.4 mg mL-1 ) and propylene glycol (PG), with a value of 248.8 mg mL-1 . The lowest solubility for OPX was in dimethyl isosorbide (9.9 mg mL-1 ), Labrafac™ (3.6 mg mL-1 ) and isostearyl isostearate (0.5 mg mL-1 ). Over the 4 days, OPX showed stability in ethanol and PG, while a notable decrease in OPX was observed in PBS and DI water at 32 ± 1°C. CONCLUSION: The physicochemical properties of OPX were characterized to find suitable excipients able to target the epidermis for topical delivery. Building on these findings, future work will focus on the development of novel topical formulation of OPX.

OBJECTIF: la production de pellicules et la maladie plus grave qui y est apparentée, la dermatite séborrhéique, touchent une grande partie des personnes à un moment donné de leur vie. La piroctone olamine, également connue sous le nom d'Octopirox® (OPX), est le sel de monoéthanolamine de la piroctone. Il s'agit d'un agent antifongique largement utilisé pour le traitement des pellicules. L'objectif de ce travail était de caractériser les propriétés physicochimiques de la piroctone olamine et de mener des études de préformulation pour le développement de nouvelles formulations topiques de ce principe actif. MÉTHODES: une méthode de chromatographie liquide à haute performance (CLHP) a été développée et validée pour l'analyse de l'OPX. Le point de fusion a été déterminé à l'aide du calorimètre à balayage différentiel (Differential Scanning Calorimetry, DSC) Q2000 (TA Instruments, États-Unis). Le coefficient de distribution (logD(Octanol/PBS) ) et le coefficient de partage (log Poctanol/eau , ou log Poe ) ont été déterminés dans le tampon phosphate salin (phosphate buffered saline, PBS) et dans l'eau désionisée (deionised, DI) à l'aide de la méthode par agitation en flacon. Toutes les expériences ont été réalisées à température ambiante. La solubilité a été déterminée de manière expérimentale. Une certaine quantité du principe actif a été ajoutée au solvant. Les échantillons ont été conservés à une température de 32 °C ± 1 °C pendant 48 h dans un bain-marie. La stabilité du composé a été déterminée à l'aide d'une gamme de solvants. Des solutions de 1 mg mL−1 ont été préparées dans les solvants correspondants. Les solutions ont été conservées et agitées tout au long de l'expérience à une température de 32°C ± 1°C. Des aliquotes ont été prélevées après 24, 48 et 96 h. RÉSULTATS: la méthode CLHP a été développée avec succès. Toutefois, les échantillons situés dans la partie inférieure de la courbe d'étalonnage ont montré des degrés inférieurs de précision et d'exactitude. Sur la base des expériences avec le DSC, le point de fusion a été observé à une température initiale de 132,4°C. Le LogD a été déterminé à 1,84. Le composé présentait la solubilité la plus élevée dans le méthanol (278,4 mg mL−1 ) et le propylène glycol (PG), avec une valeur de 248,8 mg mL−1 . L'OPX présentait la solubilité la plus faible dans l'isosorbide de diméthyle (9,9 mg.mL−1 ), le LabrafacTM (3,6 mg mL−1 ) et l'isostéarate d'isostéaryle (0,5 mg mL−1 ). Sur les 4 jours, l'OPX a montré une stabilité dans l'éthanol et le PG, tandis qu'il a diminué de manière notable dans le PBS et l'eau désionisée à une température de 32°C ± 1°C. CONCLUSION: les propriétés physicochimiques de l'OPX ont été caractérisées afin de trouver des excipients appropriés capables de cibler l'épiderme dans le cadre d'une administration topique. En s'appuyant sur ces résultats, les travaux futurs se concentreront sur le développement d'une nouvelle formulation topique de l'OPX.

An overview of the implementation of SeDeM and SSCD in various formulation developments.

The Sediment Delivery Model explains experimental analysis and quantitative assessment of the powdered substance characterizing parameters, which offer pertinent data about the material's appropriateness for direct compression (DC) of tablet, which involves mathematical modeling and Semisolid Control Diagram using software like iTCM. The SeDeM diagram expert system (DES) determines the suitability of excipients and active ingredients for DC and the ratio of API to excipient is calculated. The DC is most suitable as it saves time and makes process easy, but these technique excipients compensate for their poor flow. Thus, a new system was required to help reduce number of experiments and time for making an optimized direct compression tablet. The SeDeM DES is based on quality by design (QbD) (ICH Q8) as it evaluates critical quality attributes that affect finished product's quality. This review mainly focuses on various dosage forms like Solid, Semisolid, Liquisolid, and Solidified liquid dosage forms. These techniques mainly characterize all substances using 12 parameters, resulting 12-sided regular polygon. However, parameters may increase or decrease according to the requirement of a particular dosage form like an Orodispersible tablet 15 and a Semisolid dosage form applying 5 parameters. The rationales behind limits for indexes are justified accordingly.

Preformulation studies for the development of a microemulsion formulation from Ambrosia peruviana All, with anti-inflammatory effect

Abstract Natural products are considered an important source of the therapeutic arsenal currently available. Among these alternatives are the seeds of Ambrosia peruviana (altamisa), whose extract has shown an anti-inflammatory effect. The main objective of this work was to perform a preformulation study of Ambrosia peruviana seeds ethanolic extract, where the main factors that affect the physical, chemical, and pharmacological stability of the extract were evaluated, as well as a compatibility study by differential scanning calorimetry (DSC) analysis against different excipients. A dry extract was obtained by rotary evaporation of the seeds macerated with 96% ethanol. The anti-inflammatory activity was determined by measuring its effect on NO production in RAW 264.7 macrophages, stimulated with LPS. The results showed that the dry extract maintained its stability over time when stored at a temperature of 4 and 25ºC, demonstrating its biological activity, the content of phenolic compounds, and its physicochemical parameters remain practically invariable. However, when exposed to high temperatures (60 ºC) it was affected. The thermal analysis revelated that the behavior of most of the selected excipients and the dry extract was maintained, which indicates that it did not present incompatibilities, therefore they can be candidates for formulating a microemulsion.

Identification of the Major Degradation Pathways of Selumetinib.

Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule.