Ileo-Colon Targeting of the Poorly Water-Soluble Drug Celecoxib Using a pH-Dependent Coating in Combination with Self-Emulsifying Drug Delivery or Solid Dispersion Systems

Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined a pH-dependent coating with self-emulsifying drug delivery systems (SEDDS) or with solid dispersion systems (SD); two approaches that are often used to improve the dissolution behavior of lipophilic drugs. The dissolution behavior of various formulations of both systems was investigated. Optimized formulations with and without precipitation inhibitors were coated with the ColoPulse and the release of celecoxib was tested under non-sink conditions using an in vitro dissolution system, simulating the pH gradient of the gastrointestinal tract. The dissolution behavior of SDs with and without precipitation inhibitor (sodium dodecyl sulfate) and the SEDDS without precipitation inhibitor was negatively impacted by the coating. Control experiments indicated that components of the coating released in the dissolution medium acted as precipitation mediators. However, the SEDDS formulation with HPMC 4000 cps as a precipitation inhibitor showed excellent dissolution behavior. We hypothesize that HPMC accumulates at the oil/water interface of the emulsion thereby stabilizing the emulsion resulting in maintenance of the supersaturated state.

In-Vitro Functionality of Clozapine Biphasic Release Minitablet Using Advanced Statistical Tools

Background: The better control of the drug release with immediate effect is the major concern to achieve better therapeutic action and patient compliance. The failure of the solid dispersion complex during storage as well as in-vivo is another concern for the oral solid dosage form. Objective: The prime objective of the present study was to optimize the biphasic minitablet incorporating quality by design approach using the combination of waxy erodible and water-impermeable excipients. Exploration of Soluplus as a precipitation inhibitor and Dexolve as a solubility enhancer in oral solid dosage form was the secondary objective. Methods: The drug-Excipient compatibility study was assessed by FTIR. Clozapine was chosen as a model drug that has poor aqueous solubility. The complex was formulated using B-cyclodextrin or HP B-CD or Dexolve by kneading method. The screening of solubility enhancers and their amount were performed based on phase solubility study. The precipitation inhibitor was screened as per the parachute effect study. Immediate release minitablets were formulated using a direct compression method using different disintegrating agents. The IR minitablets were evaluated for different evaluation parameters. The sustained release minitablets was formulated by hot-melt granulation technique incorporating the Precirol ATO 5 as a waxy excipient and ethyl cellulose as water impermeable excipient. The SR minitablet was optimized using a central composite design. The amount of Precirol ATO 5 and ethyl cellulose were chosen as independent variables and % drug release at 1, 6, and 10 h was selected as responses. The designed batches were evaluated for different pre and post compressional parameters. The IR and SR minitablets were filled in a capsule as per dose requirement and evaluated for in-vitro drug release. The in-vivo plasma concentration was predicted using the Back calculation of the Wagner – Nelson approach. Results: Drug – Excipient study revealed that no significant interaction was observed. Dexolve was screened as a solubility enhancer for the improvement of the solubility of clozapine. The Soluplus was chosen as a precipitation inhibitor from the parachute effect study. The immediate-release tablet was formulated using Prosolv EASYtab SP yield less disintegration time with better flowability. The sustained release mini-tablet was formulated using Precirol ATO 5 and ethyl cellulose. Two-dimensional and three-dimensional plots were revealed the significant effect of the amount of Precirol ATO 5 and ethyl cellulose. The overlay plot locates the optimized region. The in-vitro drug release study revealed the desired drug release of the final combined formulation. The in-vivo plasma concentration-time confirms the drug release up to 12h. Conclusion: The biphasic mini-tablets were formulated successfully for better control of drug release leads to high patient compliance. The use of soluplus as a precipitation inhibitor is explored in the oral solid dosage form for a poorly aqueous drug. Prosolv EASYtab SP was incorporated in the formulation as super disintegrant. The amount of Precirol ATO 5 and ethyl cellulose had a significant effect on drug release in sustained-release minitablet. The approach can be useful in the industry.

Cocrystals of Modafinil-Nicotinic Acid: A Novel Cocrystal for Enhanced Bioavailability

In this work, we are the first to identify and report pharmaceutically effective cocrystals of the poorly soluble drug Modafinil (MOD) using a crystal engineering approach. A multi-component system of MOD with nicotinic acid (NIC) as the coformer at a 1:1 molar ratio was prepared to simultaneously improve the solubility, dissolution and bioavailability by applying a liquid assistant grinding technique. Nicotinic acid as a potential coformer for cocrystal preparation was predicted using a novel approach of the Hansen Solubility Parameter (HSP) group contribution method. Various evaluation parameters pertaining to confirm cocrystal formation, such as Fourier transformer infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and field emission scanning electron microscopy (FESEM) were carried out. Further effects of precipitation inhibitor Hydroxypropyl methyl cellulose (HPMC) on in-vivo bioavailability enhancement were also studied. MOD-NIC cocrystals formation was confirmed by integrating the results of instrumental techniques. Aqueous solubility and in-vivo pharmacokinetic study proved 5.96 and 1.88 times higher bioavailability, respectively, in the case of prepared cocrystals compared to MOD alone, whereas bioavailability further increased by 2.72 times when these cocrystals were administered in the presence of precipitation inhibitor. Hence, solid state manipulation was successful for preparing modafinil cocrystals as a potential method for illustrating several properties. The concept of cocrystals coupled with precipitation inhibitors significantly enhanced the bioavailability of modafinil.

Novel in vitro and in silico tools for the development of mesoporous silica formulations with optimal precipitation inhibitors

Formulation scientists have developed a toolkit of strategies that can improve the solubility and subsequent bioavailability of poorly soluble candidates. Amorphous formulations are especially appealing due to the significant improvement in solubility the amorphous form can provide, but must be stabilized for effective performance (Timpe, 2007). 2. The Importance of Drug Polymer Interactions in Precipitation Inhibition Polymeric “precipitation inhibitors” have seen widespread usage in the literature (Warren, 2010). The precipitation inhibition effect of polymers on precipitations is related to interference with nucleation and crystal growth (Xu, 2013). Many techniques have been reported in the literature to predict these interactions, however, they are not suitable to screening due to API and time resources required, which are not amenable to early stage pharmaceutical development. 3. Mesoporous Silica: An Emerging Formulation Technology Mesoporous silicon dioxide has emerged in recent years as a new option for stabilizing the amorphous form. Upon impregnation of the silica with a concentrated drug solution, the drug can be molecularly adsorbed and locally and sterically confined, preventing recrystallization (Ditzinger, 2018). Upon administration of mesoporous silica formulations to the body the amorphous formulation generates supersaturation which must be stabilized using precipitation inhibitors (Guzman, 2007). 4. Co-incorporation: A New Method to Combine Precipitation Inhibitors with Mesoporous Silica There has been no systematic study of how best to incorporate precipitation inhibitors into mesoporous silica formulations. The current standard practice involves combining inhibitors in a physical mixture with the drug-loaded silica, either by pestle and mortar or overhead stirring. Due to the lack of a defined protocol, there is uncertainty about how reliably the precipitation inhibitor is combined with the drug-loaded silica on a batch to batch basis. In this work, a novel co-incorporated formulation of glibenclamide and the precipitation inhibitor, HPMCAS, onto mesoporous silica was described. By co-incorporating the precipitation inhibitor, the formulation significantly outperformed the commonly applied simple physical blend due to the formation of drug-polymer interactions in the solid state. 5. In Silico Pharmaceutics: A New Method to Select Precipitation Inhibitors for Mesoporous Silica An approach that can incorporate understanding of the drug-polymer interactions with a quick and efficient screening process would be very useful. The COnductor like Screening MOdel for Real Solvents (COSMO-RS) is a quantum mechanical theory, which can be used to derive thermodynamic properties of interest. (Klamt, 1993, 1995, 2003). We proposed excess mixing enthalpies of drug and polymer could be calculated using the COSMO-RS theory. This new approach was applied to screen precipitation inhibitors for three model compounds, all of which showed a strong positive correlation between the rank assigned based on the calculated free enthalpy of mixing and the overall formulation performance. 6. Conclusion This body of work aimed to improve the processes underpinning the design and development of mesoporous silica with precipitation inhibitors. Firstly, this involved two extensive literature reviews in the area of solubility enhancement formulation technologies and precipitation inhibition. Secondly, a mechanistic rational and experimental approach was developed to improve the formulation of precipitation inhibitors with mesoporous silica, the “co-incorporation” approach significantly improved process efficiency and formulation performance. Finally, combining insights from the aforementioned review, and learnings from the mechanistic analysis of the “co-incorporation” approach, an in silico screening protocol was developed to calculate the enthalpy of interaction between drug and polymer, to identify the most optimal precipitation inhibitor for a given formulation.

Polymeric Precipitation Inhibitor Assisted Supersaturable SMEDDS of Efavirenz Based on Experimental Observations and Molecular Mechanics

Background: Supersaturable SMEDDS, a versatile dosage form, was investigated for improving the biopharmaceutical attributes and eradicating the food effect of poorly water soluble drug efavirenz. Objective: The present research pursues development of efavirenz loaded supersaturable self-microemulsifying drug delivery system (SS SMEDDS) for improving biopharmaceutical performance. Methods: Preformulation studies were carried out to determine the optimized range of lipid excipients to develop stable supersaturated SMEDDS (ST SMEDDS). The SS SMEDD formulation was prepared by adding hydroxypropyl methylcellulose as a polymeric precipitation inhibitor. The developed SS SMEDDS were evaluated for supersaturation behavior by performing in vitro supersaturation studies and molecular simulations by in silico docking. Dissolution was performed in biorelevant media to simulate fed/fasted conditions in gastrointestinal regions. Absorption behavior was determined through in vivo pharmacokinetics approach. Results: The optimized ST SMEDDS formulation containing Maisine® CC, Tween 80 and Transcutol-P exhibited thermodynamic stability with quick rate of emulsification. The optimized SS SMEDDS containing suitable polymeric precipitation inhibitor exhibited enhanced efavirenz concentration in in vitro supersaturation test. The theoretical simulations by molecular docking revealed strong intermolecular interactions with a docking score of -3.004 KJ/mol. The dissolution performance of marketed product in biorelevant dissolution media inferred the existence of food effect in the dissolution of efavirenz. However, in SS SMEDDS, no significant differences in drug release behavior under different fasted/fed conditions signify that the food effect was neutralized. In vivo pharmacokinetics revealed a significant increase in the absorption profile of efavirenz from SS SMEDDS than that of ST SMEDDS and marketed product. Conclusion: The designed delivery system indicated promising results in developing an effectual EFV formulation for HIV treatment.

A Review on Precipitation inhibitors in supersaturable self emulsifying drug delivery system

The super saturable formulation has been widely used as an effective method to improve solubility and oral absorption of poorly aqueous-soluble drugs. When the super saturable formulation comes in contact with gastrointestinal fluids, its drug concentration goes over the equilibrium solubility, but this state does not exist for too long, the drug may precipitate before being absorbed, which minimizes the efficacy and bioavailability of the drug. Therefore, it is necessary to inhibit or retard the precipitation of drugs to achieve the maximum benefits of the super saturable formulation. Polymers (watersoluble and insoluble) are the commonly used excipients to inhibit precipitation. Cyclodextrins and surfactants are the other two excipients used as precipitation inhibitors. In some of the cases, even solid carriers can effectively retard precipitation. The precipitation inhibitors (PI) have the capacity to maintain a super saturable state of the formulation in GI for a particular time period. Therefore, it is important to properly select the precipitation inhibitor; too frequently used methods to select precipitation inhibitor are casting film method and solvent-shift method. Such selected and successfully used precipitation inhibitors are HPMC E5LV, PVP K17, HPMC E5, soluplus, poloxamer 407, HPMCAS, maltodextrin (mal) and microcrystalline cellulose (mcc). Since the super saturable technique has been widely used for delivering poorly water-soluble drugs like ezetimibe, indirubin, feno fibrate, butyl paraben and rosu vastatin calcium. There is a necessity for bio relevant evaluation of supersaturation/precipitation because simple methods like dissolution tests cannot be bio relevant in a supersaturation/precipitation context. Some of the important factors like sink versus non-sink conditions, hydrodynamic, medium selection and temperature play a vital role in the evaluation of in-vitro supersaturation