Mechanical Activation by Ball Milling as a Strategy to Prepare Highly Soluble Pharmaceutical Formulations in the Form of Co-Amorphous, Co-Crystals, or Polymorphs (original) (raw)
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Overview of milling techniques for improving the solubility of poorly water-soluble drugs
Milling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a "top-down" approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility. The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation). Technology advancements in milling now enable the production of drug micro-and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement.
Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates
Advanced Drug Delivery Reviews, 2007
The increasing prevalence of poorly soluble drugs in development provides notable risk of new products demonstrating low and erratic bioavailabilty with consequences for safety and efficacy, particularly for drugs delivered by the oral route of administration. Although numerous strategies exist for enhancing the bioavailability of drugs with low aqueous solubility, the success of these approaches is not yet able to be guaranteed and is greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering offers a number of routes to improved solubility and dissolution rate, which can be adopted through an in-depth knowledge of crystallisation processes and the molecular properties of active pharmaceutical ingredients. This article covers the concept and theory of crystal engineering and discusses the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles. Also considered within this review is the influence of crystallisation conditions on crystal habit and particle morphology with potential implications for dissolution and oral absorption.
2017
Tablets have been choice of manufacturers over the years due to their comparatively low cost of manufacturing, packaging, shipping, and ease of administration; also have better stability and can be considered virtually tamper proof. A major challenge in formulation development of the tablets extends from lower solubility of the active agent to the elaborated manufacturing procedures for obtaining a compressible granular material. Moreover, the validation and documentation increases, as the numbers of steps increases for an industrially acceptable granulation process. Spherical crystallization (SC) is a promising technique, which encompass the crystallization, agglomeration, and spheronization phenomenon in a single step. Initially, two methods, spherical agglomeration, and emulsion solvent diffusion, were suggested to get a desired result. Later on, the introduction of modified methods such as crystallo‑co‑agglomeration, ammonia diffusion system, and neutralization techniques overcame the limitations of the older techniques. Under controlled conditions such as solvent composition, mixing rate and temperature, spherical dense agglomerates cluster from particles. Application of the SC technique includes production of compacted spherical particles of drug having improved uniformity in shape and size of particles, good bulk density, better flow properties as well as better solubility so SC when used on commercial scale will bring down the production costs of pharmaceutical tablet and will increase revenue for the pharmaceutical industries in the competitive market. This review summarizes the technologies available for SC and also suggests the parameters for evaluation of a viable product.
Indian Journal of Pharmaceutical Sciences, 2009
Yadav, et al.: Co-crystals to Modify Physicochemical Properties of API's Crystal form can be crucial to the performance of a dosage form. This is especially true for compounds that have intrinsic barriers to drug delivery, such as low aqueous solubility, slow dissolution in gastrointestinal media, low permeability and first-pass metabolism. The nature of the physical form and formulation tends to exhibit the greatest effect on bioavailability parameters of water insoluble compounds that need to be given orally in high doses. An alternative approach available for the enhancement of drug solubility, dissolution and bioavailability is through the application of crystal engineering of co-crystals. The physicochemical properties of the active pharmaceutical ingredients and the bulk material properties can be modified, whilst maintaining the intrinsic activity of the drug molecule. This article covers the advantages of co-crystals over salts, solvates (hydrates), solid dispersions and polymorphs, mechanism of formation of co-crystals, methods of preparation of co-crystals and application of cocrystals to modify physicochemical characteristics of active pharmaceutical ingredients along with the case studies. The intellectual property implications of creating co-crystals are also highly relevant.
Co-Crystallization: A Novel Approach to Enhance the Dissolution of Poorly Soluble Drugs
2019
Approximately 40% of newly synthesized drugs are not able to enter market due to biopharmaceutical issues like poor solubility and poor permeability. Most number of drugs marketed is administered orally hence solubility enhancement plays a major role. There are different techniques to upgrade the dissolvability of inefficiently soluble drugs including pro-drug approach, salt formation, particle size reduction, complexation and solid dispersion. Out of all other techniques, salt formation is one of majorly used technique to improve physicochemical characteristics of drugs which includes formation of ionic bond. But nowadays development of co-crystals has evolved as a suitable technique towards improving the dissolvability and bioavailability of ineffectively soluble drugs that includes non-ionic bond formation. In this paper a brief and accurate precis of pharmaceutical co-crystals is stated with specific spotlight on co-crystal preparation methodologies, mechanism of co-crystal form...
AAPS PharmSciTech, 2015
As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as th...
Pharmaceutical Co-crystal : An Emerging Technique to enhance Physicochemical properties of drugs
International Journal of ChemTech Research, 2020
Major constraints in development of new product are poor aqueous solubility, stability and low oral bioavailability, low permeability. As majority of drugs marketed worldwide are administered by oral route and about 40% -50% of the new molecular entities were never invade into the market because of such biopharmaceutical issues.So issues related to poor physiochemical property of an active pharmaceutical ingredient (API) can be resolved using cocrystallization approach.Crystallization emerge as potential technique for enhancement of solubility of poorly aqueous soluble drugs also helps to improve physicochemical with preserving the pharmacological properties of the API . Cocrystals are solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates/hydrates nor simple salts. It is multicomponent system in which one component is API and another is called coformer. Cofo...
New Trends in the Co-crystallization of Active Pharmaceutical Ingredients
Journal of Applied Pharmaceutical Science
Pharmaceutical materials science being a fundamental branch that continuously provides important insights, theories, and technologies to formulation sciences. The recent advances in this area have brought the possibility to produce pharmaceutical materials by design. In particular, the formation of co-crystals, i.e. crystalline molecular complexes of two-or more neutral molecules, represents a potential route to achieve pharmaceutical materials with improved properties of interest, including dissolution rate and stability under conditions of high relative humidity. Co-crystals consists of API and a stoichiometric amount of a pharmaceutically acceptable co-crystal former. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to address physical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API. These can be constructed through several types of interaction, inc...
Spherical crystallization -A novel drug delivery system
INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES , 2011
Today, the tablet is the most popular dosage form, covering around 50% of total oral drug delivery system and accounting 75% of all pharmaceutical preparation produced .It promotes statbility, portability and acceptable patient compliance .The quality of solid dosage form is primarily influenced by micromeritic characteristics such as the shape and size of drug crystal, especially in the case of poorly soluble drugs. To improve the dissolution rate of poorly soluble drugs, fine crystals are referred and this micronisation can change drug powder properties such as wettability, compressibility, packability and flow. Further, it is more beneficial to convert micro crystalline drugs into an agglomerated form using spherical crystallization technique. The resulting spherically agglomerated crystals can be directly prepared into a tablet, thus direct tabletting saves time and reduces cost .General methods of spherical crystallization are spherical agglomeration, emulsion, solvent diffusion method, ammonia diffusion method, neutralization method .The principle steps involved in the process of sc are flocculation zone, zero growth zone, fast growth zone, constant size zone .There is a wide application of spherical crystallization:-improvement of flow ability, compressibility of poorly compressible drug, masking bitter taste of drug, improving solubility and dissolution rate of poorly soluble drug and thus improve bioavailability of drug.
American Journal of Drug Discovery, 2014
Nowadays various techniques have been applied for the improvement of physicochemical properties such as solubility, bioavailability, stability and hygroscopic nature of pharmaceutical solids without effecting the biochemical composition of the active pharmaceutical ingredients (API). Supramolecular approach specially the crystal engineering technique is one of the best techniques which play an important role to improve the physico-chemical, thermal and mechanical properties of drug molecules. Crystal engineering approach offers a number of routes such as co-crystallization, polymorphism, hydrate and salt formation with the help of which drug molecules with good physico-chemical behavior can be prepared. This article covers the concept of supramolecular chemistry and crystal engineering approach for the preparation of co-crystals and their application in pharmaceutical industries.