In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam–Copovidone Amorphous Solid Dispersion
Abstract:As the pipeline for poorly soluble compounds continues to grow, drug degradation during melt extrusion must be addressed. We present a novel method for stabilizing a thermally labile drug substance while preserving its physical stability and even improving its dissolution performance. In a previous study, we found that incorporating meglumine during extrusion of meloxicam results in chemical stabilization that cannot be achieved using process optimization alone. The purpose of this study is to understand the m… Show more
“…EE is the most used Eudragit in the goal to improve drug solubility by formulating ASDs, acting either as a polymeric matrix [ 50 , 51 , 63 , 66 ] or as a pH modifying agent [ 62 ]. This high demand is justified by the fact that EE has a good thermal stability and is a thermoplastic polymer, making it easier to process during HME due to its very low Tg.…”
Section: Hot Melt Extrusionmentioning
confidence: 99%
“…Another approach in the development of drug delivery systems with Eudragit polymers that should be highlighted is the use of blends with polymers of different classes and with specific properties. These blends can be used to modulate the drug release, improve the flow properties and assure the stability of the formulations [ 52 , 62 , 133 , 143 ]. Due to the high number of available polymers for pharmaceutical use, the study of blends with Eudragits can be considered a field to be explored in the development of new drug delivery systems by HME and 3D printing.…”
Eudragit® polymers are polymethacrylates highly used in pharmaceutics for the development of modified drug delivery systems. They are widely known due to their versatility with regards to chemical composition, solubility, and swelling properties. Moreover, Eudragit polymers are thermoplastic, and their use has been boosted in some production processes, such as hot melt extrusion (HME) and fused deposition modelling 3D printing, among other 3D printing techniques. Therefore, this review covers the studies using Eudragit polymers in the development of drug delivery systems produced by HME and 3D printing techniques over the last 10 years. Eudragit E has been the most used among them, mostly to formulate immediate release systems or as a taste-masker agent. On the other hand, Eudragit RS and Eudragit L100-55 have mainly been used to produce controlled and delayed release systems, respectively. The use of Eudragit polymers in these processes has frequently been devoted to producing solid dispersions and/or to prepare filaments to be 3D printed in different dosage forms. In this review, we highlight the countless possibilities offered by Eudragit polymers in HME and 3D printing, whether alone or in blends, discussing their prominence in the development of innovative modified drug release systems.
“…EE is the most used Eudragit in the goal to improve drug solubility by formulating ASDs, acting either as a polymeric matrix [ 50 , 51 , 63 , 66 ] or as a pH modifying agent [ 62 ]. This high demand is justified by the fact that EE has a good thermal stability and is a thermoplastic polymer, making it easier to process during HME due to its very low Tg.…”
Section: Hot Melt Extrusionmentioning
confidence: 99%
“…Another approach in the development of drug delivery systems with Eudragit polymers that should be highlighted is the use of blends with polymers of different classes and with specific properties. These blends can be used to modulate the drug release, improve the flow properties and assure the stability of the formulations [ 52 , 62 , 133 , 143 ]. Due to the high number of available polymers for pharmaceutical use, the study of blends with Eudragits can be considered a field to be explored in the development of new drug delivery systems by HME and 3D printing.…”
Eudragit® polymers are polymethacrylates highly used in pharmaceutics for the development of modified drug delivery systems. They are widely known due to their versatility with regards to chemical composition, solubility, and swelling properties. Moreover, Eudragit polymers are thermoplastic, and their use has been boosted in some production processes, such as hot melt extrusion (HME) and fused deposition modelling 3D printing, among other 3D printing techniques. Therefore, this review covers the studies using Eudragit polymers in the development of drug delivery systems produced by HME and 3D printing techniques over the last 10 years. Eudragit E has been the most used among them, mostly to formulate immediate release systems or as a taste-masker agent. On the other hand, Eudragit RS and Eudragit L100-55 have mainly been used to produce controlled and delayed release systems, respectively. The use of Eudragit polymers in these processes has frequently been devoted to producing solid dispersions and/or to prepare filaments to be 3D printed in different dosage forms. In this review, we highlight the countless possibilities offered by Eudragit polymers in HME and 3D printing, whether alone or in blends, discussing their prominence in the development of innovative modified drug release systems.
“…Copovidone, the polymer used in the meloxicam study, contains acetyl groups, decreases the microenvironment pH of the composition, promoting MLX degradation via hydrolysis ( 121 ). Understanding the polymer effects on the microenvironment pH and its impact on MLX degradation, the pH modifier meglumine, formed a salt between its secondary amine and the anionic carbonyl present on MLX, stabilizing the composition and eliminating degradation ( 121 , 127 ). Fig.…”
Section: Recent Innovations In Hot-melt Extrusion To Prevent Thermal mentioning
Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.
“…Polymorphism is the ability of an element or compound to crystallize in more than one crystalline form. Different polymorphs of drugs are chemically identical, but they exhibit different physicochemical properties including solubility, melting point, density, texture, stability 41,44 .…”
Section: (D) Modification Of Crystal Habit 22mentioning
The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Solubility is essential for the therapeutic effectiveness of the drug, independent of the route of administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. Poorly soluble drugs are often a challenging task for formulators in the industry Conventional approaches for enhancement of solubility have limited applicability, especially when the drugs are poorly soluble simultaneously in aqueous and in non-aqueous media. Drug with poor water solubility cause slow dissolution rates, generally show erratic and incomplete absorption leading to low bioavailability when administered orally. Solubilization may be affected by cosolvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion, and change in polymorph. Some new technologies are also available to increase the solubility like micro emulsion, self-emulsifying drug delivery system and supercritical fluid technology. This present review details about the different approaches used for the enhancement of the solubility of poorly water-soluble drugs include particle size reduction, nanonization, pH adjustment, solid dispersion, complexation, co‐solvency, hydrotropy etc. The purpose of this article is to describe the techniques of solubilization for the attainment of effective absorption and improved bioavailability.
Keywords: Solubility, Solubility Enhancement, bioavailability, solid dispersion, Solid Dispersion, Solubilization.
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