Design Of Pharmaceutical Formulations Research Articles

Insulin Stabilization Designs for Enhanced Therapeutic Efficacy and Accessibility.

ConspectusInsulin has remained indispensable in the treatment of diabetes since it was first discovered in 1921. Unlike small molecular drugs, insulin and other protein drugs are prone to degradation when exposed to elevated temperatures, mechanical agitation during transportation, and prolonged storage periods. Therefore, strict cold-chain management is crucial for the insulin supply, requiring significant resources, which can limit the access to insulin, particularly in low-income areas. Moreover, although insulin formulations have advanced tremendously in the last century, insulin treatment still imposes a challenging regimen and provides suboptimal outcomes for the majority of patients. There is an increasing focus on pursuing improved pharmacology, specifically on safer, more user-friendly insulin therapies that minimize the self-management burden. These challenges underscore the need for developing novel insulin formulations with improved stability that are compatible with advanced insulin therapy.Insulin stabilization can be achieved through either chemical modification of insulin or formulation component design. Inspired by insulin-like peptides from invertebrates, we have developed novel stable insulin analogs based on a fundamental understanding of the insulin receptor engagement for insulin bioactivity. We created a novel four-disulfide insulin analog with high aggregation stability and potency by introducing a fourth disulfide bond between a C-terminal extended insulin A-chain and residues near the C-terminus of the B-chain. In an effort to stabilize insulin in its monomeric state to develop ultrafast-acting insulin with rapid absorption upon injection, we have developed a series of structurally miniaturized yet fully active insulin analogs that do not form dimers due to the lack of the canonical B-chain C-terminal octapeptide. Additionally, our study provided strategies for expanding the scope of cucurbit[7]uril (CB[7])-assisted insulin stabilization by engineering safe and biodegradable CB[7]-zwitterionic polypeptide excipients. We also explored insulin N-terminal substitution methods to achieve pH-dependent insulin stabilization without prolonging the duration of action.This Account describes our exploration of engineering stable insulin analogs and formulation design strategies for stabilizing insulin in aqueous solutions. Beyond conventional stabilization strategies for insulin injections, the unmet challenges and recent innovations in insulin stabilization are discussed, addressing the growing demand for alternative, less invasive routes of insulin administration. Additionally, we aim to provide a thorough overview of insulin stabilization from the perspective of commercially available insulin drugs and common pharmaceutical engineering practices in the industry. We also highlight unresolved insulin stabilization challenges and ongoing research strategies. We anticipate that further emphasis on collective efforts of protein engineering, pharmaceutical formulation design, and drug delivery will inform the development of stable and advanced insulin therapy.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80°C to 220°C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher thanthat of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

COSMOPharm: Drug-Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC.

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.

Exploring the Role of Artificial Intelligence and Machine Learning in Pharmaceutical Formulation Design

Exploring the Role of Artificial Intelligence and Machine Learning in Pharmaceutical Formulation Design

Ibuprofen Formulations: Permeability and Biodegradability Comparison Depending on the Type of Formulation

This study assesses ibuprofen’s permeability to different formulations and their biodegradation. Hydrogel, organogel, Eucerin ointment, silicone ointment, and zinc ointment were investigated. The objective was to comprehensively evaluate the therapeutic efficacy and environmental implications of these formulations. Diverse formulations were examined through the utilisation of Franz diffusion chambers to evaluate the in vitro permeability of both ibuprofen and ibuprofenate sodium. Moreover, biodegradation studies of the obtained formulations were carried out with activated sludge. The activity of the inoculum was confirmed by using SDS as a reference compound. The experimental settings used (carbon content and inoculum volume) were selected based on the criteria set by the OECD guidelines. Relevant parameters pertaining to the biodegradation process were estimated, including biodegradation values (%B) at specific time points, half-lives of initial compounds and API-containing formulations, and degradation phases (lag phase I; degradation phase II, and plate phase III). For comparison purposes, biodegradation studies were also carried out for the initial IBU and IBUNa compounds under the same conditions. The environmental implications of these findings underscore the need for a balanced consideration of therapeutic efficacy and environmental sustainability in pharmaceutical formulation design. This study provides valuable insights for pharmaceutical researchers, environmental scientists, and regulatory bodies involved in the development and assessment of drug formulations. The proposed method of removing NSAIDs from aquatic ecosystems is a cheaper alternative to techniques such as reverse osmosis, oxidation, UV degradation, or photolysis, which have not found practical use owing to the generation of toxic sludge or high capital and operating costs.

CRITICAL ANALYSIS OF POWDER FLOW BEHAVIOUR OF DIRECTLY COMPRESSIBLE COPROCESSED EXCIPIENTS

The aim of this pre-formulation study was to adopt simple linear regression modelling and correlation statistics to understand the associations between pharmacopoeial powder test methods using datasets generated from five commercial brands of directly compressible excipients with a specific focus to inferential implications in formulation design. Powder characterization was conducted using protocols defined in Chapter &lt;1174&gt; and &lt;616&gt; of the United States Pharmacopoeia (USP41-NF36). The study adopted a linear regression modelling analytics and correlation statistics using the fitting algorithm of OriginPro® (OriginPro, Version 2021b, OriginLab Corporation, Northampton, MA, USA). In the results, the modulus of Pearson’s product moment correlation coefficient was used to measure the strength of the linear association between test variables and a correlation matrix generated. Strong positive correlation modulus of Hausner’s Ratio (HR) with Carr’s index (r=+0.999) and static angle of repose (r=+0.932) were evident. Bulk density strongly correlates with tap density in the positive direction (r=+0.911). Tap density also shows a slight negative correlation with HR (r=-0.230), Carr’s index (r=-0.228), and static angle of repose (r==-0.421), while Carr’s index strongly correlated with static angle of repose (r=+0.933). In conclusion, modelling bivariate powder flow datasets has provided a powerful but simplistic statistical relationship for characterizing the modulus of association between HR, Carr’s index, and static angle of repose of the model excipients useful in preformulation design of pharmaceutical formulations.

The Potential of Quality Target Product Profile in the Optimization of Nanoemulsions

Abstract: The application of Quality Target Product Profile (QTPP) in optimizing nanoemulsion (NEM) shows immense potential in advancing pharmaceutical formulation design for effective drug delivery. By aligning QTPP with nanoemulsion attributes, this approach offers a pathway to tailored formulations that meet specific therapeutic objectives and responses. Incorporating QTPP facilitates informed choices in formulating design, covering pivotal factors like stability, drug re-lease kinetics, bioavailability, and precise targeting. Moreover, this review extensively explores the real-world application of QTPP-guided tactics in refining nanoemulsion optimization. It high-lights their pivotal role in anticipating and regulating in vivo responses, encompassing vital as-pects like pharmacokinetics and pharmacodynamics. By conducting thorough examinations of case studies and research outcomes, this article clarifies the effectiveness of aligning QTPP crite-ria with NEM characteristics. This approach fosters the creation of customized formulations pre-cisely suited to achieve distinct therapeutic objectives. This review amalgamates contemporary insights into harnessing QTPP for nanoemulsion optimization, illuminating its capacity to stream-line formulation design, amplify treatment effectiveness by desiring drug release, and catalyze transformative shifts in pharmaceutical research.

Pharmaceutical formulation design for enhancing solubility, stability, and bioavailability of poorly water-soluble drugs: An Analytical Perspective

The development of pharmaceutical formulations for drugs with poor water solubility presents significant challenges in achieving desired therapeutic outcomes. These drugs have limited solubility, which result in suboptimal bioavailability, reduced stability, and compromised efficacy. To overcome challenges, formulation strategies required to enhance drug solubility, stability, and bioavailability. Several approaches explored in pharmaceutical formulation design to address the solubility issues with poorly water-soluble drugs. These approaches particle size reduction, solid dispersion, lipid-based formulations, cyclodextrin complexation, and nanotechnology-based delivery systems. Particle size reduction techniques, such as micronization and nanonization, can significantly increase the surface area and improve dissolution rates, thereby enhancing drug solubility. Techniques such as hot melt extrusion and spray drying help disperse medications with low solubility into water-loving carriers, which boosts their solubility and ability to dissolve. Formulations that are lipid-based, like self-emulsifying drug delivery systems (SEDDS) and lipid nanoparticles, can optimize solubility and absorption of drugs by taking advantage of naturally occurring physiological pathways connected to lipid digestion and absorption. Furthermore, cyclodextrins have the capability to form complexes that aid in the increased solubility and preserving stability of medications that have little water solubility.

Revisiting the Solubility–Permeability Relationship with Hydrophobic Drug Umifenovir in Pluronic Solutions: Impact of pH and Co-Solvent

This study describes the influence of pluronic F-127 (F-127) and ethanol (EtOH) on the solubility of umifenovir (UMF) in buffer solutions of pH 2.0 and pH 7.4, and its permeability through cellulose membranes. A 44.4-fold greater UMF solubility in acidic medium as compared to an alkaline one was estimated at 310.15 K. The concentration of UMF in the saturated solution was enhanced by the interaction with F-127 micelles. The combined positive effect of EtOH and F-127 on the solubility was estimated. The aggregation number of F-127 micelles in the presence of 10% and 20% ethanol appeared to be reduced by 2.1-fold and 4.1-fold, respectively, as compared to buffer pH 7.4. The presence of ethanol in buffer pH 7.4 solution provided better solvent conditions but inhibited the formation of F-127 micelles. The impact of UMF on the aggregation number of F-127 was not pronounced and was expressed only by a slight increase of 1 and 3 units in 10% and 20% EtOH, respectively. According to the values of zeta potential, addition of EtOH reduced the stability of the system. The permeation of UMF in buffer pH 7.4 measured through the cellulose membrane MWCO 12-14 kDa was increased 1.4-fold by 10% EtOH. An increase in EtOH content to 20% reduced this effect to 1.2-fold. Decreasing effect of 1.5% F-127 on the permeability was inhibited by using 10% EtOH. The solution containing 1.5% F-127 and 10% EtOH was shown to be an advantageous system for UMF in view of the solubility-permeability balance. The authors suppose the findings of the study to be useful for the design of pharmaceutical formulations based on UMF antiviral drugs.

Integrated computer-aided formulation design: A case study of andrographolide/ cyclodextrin ternary formulation

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists, which is time-consuming, high cost and waste materials. This research aims to integrate various computational tools, including machine learning, molecular dynamic simulation and physiologically based absorption modeling (PBAM), to enhance andrographolide (AG) /cyclodextrins (CDs) formulation design. The lightGBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy. AG/γ-CD inclusion complexes showed the strongest binding affinity, which was experimentally validated by the phase solubility study. The molecular dynamic simulation was used to investigate the inclusion mechanism between AG and γ-CD, which was experimentally characterized by DSC, FTIR and NMR techniques. PBAM was applied to simulate the in vivo behavior of the formulations, which were validated by cell and animal experiments. Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate (TPGS) significantly increased the intracellular uptake of AG in MDCK-MDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers. The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills, respectively. In conclusion, this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility, dissolution rate and bioavailability. The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.

Comparative Stability of Two Anti-hyperpigmentation Agents: Kojic Acid as a Natural Metabolite and Its Di-Palmitate Ester, Under Oxidative Stress; Application to Pharmaceutical Formulation Design.

Purpose: Kojic acid (KA) a natural metabolite and its dipalmitate ester, kojic acid dipalmitate(Kadp) are both prescribed to treat skin hyperpigmentation. Stress test reveals the intrinsicstability of active ingredients and leads to selection of the suitable formulations. This researchevaluates the comparative stability of KA and its di-palmitate ester under liquid oxidative stress. Methods: The HPLC-UV/PDA method with a C18 column was utilized. Liquid oxidative stresswas induced using hydrogen peroxide (H2O2). Degradation was separately induced for eachdrug, and they were compared to each other. Results: Kadp degraded more rapidly in similar liquid oxidative stress conditions than KA did.The superior degradation model was the first order for both drugs based on the mean percentage error (MPE) values, indicating the dependency of the reaction rate on the initial concentrationof the reactive substance. Ring opening was proposed as the most possible theory for KA andKadp oxidative degradation. Conclusion: It is suggested to use KA instead of Kadp in less stable formulations, such asextemporaneous preparations. The incorporation of antioxidant excipients in Kadp formulationsis recommended for yielding better stability results. Formulating Kadp in the internal phase ofo/w emulsion formulations may protect this susceptive molecule from oxidative degradationduring the shelf life of the pharmaceutical preparation. Further studies are required to study theexact mechanism of the degradation process.

Measurement and correlation of solubility data for atorvastatin calcium in pure and binary solvent systems from 293.15 K to 328.15 K

The solubility of Atorvastatin calcium (ATV) in 11 kinds of mono-solvents and binary solvent mixture (acetone + water) of different ratio was measured by typical static method combined with ultraviolet (UV) spectrophotometry within the temperature range from 293.15 K to 328.15 K under standard atmospheric pressure. The solubility data was correlated by the modified Apelblat equation, van't Hoff equation, CNIBS/R-K equation, Sun model and NRTL model. The mole fraction solubility of ATV increased with rising temperature and the mole fraction composition of acetone in binary solvent mixture of acetone + water. In the case studied, the experimental data and calculated data of the five models have good correlation. Furthermore, the overall root mean square deviation (ORMSD) of the modified Apelblat equation is lowest in mono-solvents, and the NRTL model has the lowest value in a binary solvent system, which suggests that the two models have the most suitable fitting efficiency for the experimental solubility data of ATV.. Additionally, the van't Hoff equation was used to calculate and evaluate the thermodynamic properties of the ATV dissolution process, including enthalpy (∆Hsol0), entropy (∆Ssol0) and Gibbs free energy (∆Gsol0). The solubility data and corresponding thermodynamic models provided in this work have certain reference value for the crystallization, purification and pharmaceutical formulation design of ATV.

Solubility and dissolution thermodynamic properties of Mequindox in binary solvent mixtures

The solubility of Mequindox(MEQ) in two kinds of binary mixtures(acetone+isopropanol; N-propanol+N-butanol) with different ratio was determined by shake flask method through UV–Vis spectrophotometer over the temperature from 293.15 to 323.15 K at atmospheric pressure(p = .1 MPa). The results showed that the solubility of mequindox in binary solvent mixtures was increased with temperature raised in the investigated temperature range. In the binary-solvent of acetone and isopropanol, the data was increased as the mole fraction of acetone increased. However, the solubility of MEQ was not significantly changed in the mixed solvents of N-propanol and N-butanol with different ratio. Furthermore, thermodynamic models including the modified Apelblat equation, λh equation, GSM equation and the Jouyban-Acree model were used to correlate the experimental data. In addition, thermodynamic properties, enthalpy (△H0sol), entropy (△S0sol) and Gibbs free energy (△G0sol), were calculated and analyzed in the dissolution process. This study provides a certain theoretical basis for the isolation purification and pharmaceutical formulation design of MEQ.

In Situ Crystal Growth Rate Distributions of Active Pharmaceutical Ingredients.

Single-particle tracking of crystal growth performed in situ enables substantial improvements in the signal-to-noise ratio (SNR) for recovered crystal nucleation and growth rates by nonlinear optical microscopy. Second harmonic generation (SHG) is exquisitely sensitive to noncentrosymmetric crystals, including those produced by many homochiral active pharmaceutical ingredients (APIs). Accelerated stability testing at elevated temperatures and relative humidity informs design of pharmaceutical formulations. In the present work, we demonstrate reduction in the Poisson noise associated with the finite number of particles present in a given field of view through continuous monitoring during stability testing. Single-particle tracking enables recovery of crystal growth rates of individual crystallites and enables unambiguous direct detection of nucleation events. Collectively, these capabilities provide significant improvements in the signal-to-noise for nucleation and crystal growth measurements, corresponding to approximately an order of magnitude reduction in anticipated measurement time for recovery of kinetics parameters.

On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

Solubility and thermodynamics of polymorphic indomethacin in binary solvent mixtures

The significant effect of solvent mixtures on the dissolution behavior of indomethacin (IMC) was systematically studied. Experimental measurements were carried out using an in-situ attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrometer. Three thermodynamic models were used to correlate the experimental data to determine the solubilities of α- and γ-form IMC in three representative systems, including acetone–heptane, acetone–water and ethanol–water at temperatures ranging from 293 K to 318 K under atmospheric pressure. The acetone–water mixture has the largest dissolving capacity for IMC among the three studied solvent mixtures, and generates “cosolvent effect”. This effect is associated with the strong hydrogen-bond interaction between acetone and water. Notably, it is found that solvent–cosolvent mixtures with solubility parameters of 21 MPa0.5–24 MPa0.5 are suitable for solubility improvement in the design of pharmaceutical formulations of IMC. The solvent and antisolvent can be chosen in this order: δantisolvent < δsolvent < 21 MPa0.5 or δantisolvent > δsolvent > 24 MPa0.5 for the antisolvent crystallization of IMC. Our analysis strongly demonstrates that the solubility parameter can be a simple and efficient tool in preliminary solvent screening. However, the relationship between the solubility parameter and the resulting polymorphic form in antisolvent crystallization requires further study to achieve its potential applicability in polymorphic control.

Predicting complexation performance between cyclodextrins and guest molecules by integrated machine learning and molecular modeling techniques

Most pharmaceutical formulation developments are complex and ideal formulations are generally obtained after extensive experimentation. Machine learning is increasingly advancing many aspects in modern society and has achieved significant success in multiple subjects. Current research demonstrated that machine learning can be adopted to build up high-accurate predictive models in drugs/cyclodextrins (CDs) systems. Molecular descriptors of compounds and experimental conditions were employed as inputs, while complexation free energy as outputs. Results showed that the light gradient boosting machine provided significantly improved predictive performance over random forest and deep learning. The mean absolute error was 1.38 kJ/mol and squared correlation coefficient was 0.86. The evaluation of relative importance of molecular descriptors further demonstrated the key factors affecting molecular interactions in drugs/CD systems. In the specific ketoprofen–CD systems, machine learning model showed better predictive performance than molecular modeling calculation, while molecular simulation could provide structural, dynamic and energetic information. The integration of machine learning and molecular simulation could produce synergistic effect for interpreting and predicting pharmaceutical formulations. In conclusion, the developed predictive models were able to quickly and accurately predict the solubilizing capacity of CD systems. Current research has taken an important step toward the application of machine learning in pharmaceutical formulation design.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review.

This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

Application of Nanotechnology in Pharmaceutical Formulation Design and Development

Application of Nanotechnology in Pharmaceutical Formulation Design and Development

Solubility enhancement of ibuprofen using tri-ureasil-PPO hybrid: structural, cytotoxic, and drug release investigation

Herein, we used tri-ureasil organic–inorganic hybrid material (tU5000) in order to enhance the solubility of nonsteroidal anti-inflammatory drugs and fine tuning the drug delivery profile. For the first time, we used tU5000 as a film-forming agent in order to provide an alternative vehicle for transdermal drug delivery systems which the cell viability of practically 100 % for the highest and the lowest tested concentrations of pure tU5000 indicated that the material was not cytotoxic. The physicochemical properties of the tU5000 drug carrier and drug-loaded hybrids were systematically studied using powder X-ray diffraction, differential scanning calorimetry, small-angle X-ray scattering, and Fourier-transform infrared spectroscopy. The structural changes of tU5000 as well as the relationships between the drug content and in vitro drug release behaviors were investigated. The results showed that the ibu molecules were homogeneously distributed in the tU5000 xerogels contributing to fine-tuning the drug delivery profile. Considering the ability to incorporated high drug content, simple and mild preparation procedure by one-pot sol–gel route, high stability of the materials, sustained-release property, this class of hybrid based on polymers and inorganic compounds may have potential applications in the design of pharmaceutical formulation as ophthalmic (contact lenses), transdermal (patches) and implantable (soft tissue) drug delivery systems.