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Saharan et al. Dissolution Enhancement of Drugs Reprinted from
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African Index Medicus, Open-J-Gate, Directory of Open Access Journals (DOAJ), Socolar, Saharan et al. Dissolution Enhancement of Drugs International Journal of Health Research

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The Editorial Office International Journal of Health Research Madonna University, Elele Campus, Rivers State E-mail: [email protected] or [email protected] Saharan et al. Dissolution Enhancement of Drugs International Journal of Health Research, June 2009; 2(2): 107-124 (e222p3-20)
Poracom Academic Publishers. All rights reserved. Review Article
Dissolution Enhancement of Drugs.
Part I: Technologies and Effect of Carriers
Received: 03-Dec-08 Revised: 12-Apr-09
Accepted: 05-May-09
Abstract

For complete absorption and good bioavailability of orally Vikas A Saharan1
administered drug, the drug must be dissolved in gastric fluids. Dissolution of drug is the rate-controlling step which Vipin Kukkar1
determines the rate and degree of absorption. Drugs with slow dissolution rates generally show erratic and incomplete Mahesh Kataria1
absorption leading to low bioavailability when administered orally. Since aqueous solubility and slow dissolution rate of Manoj Gera1
BCS class II and class IV drugs is a major challenge in the Pratim K Choudhury2
drug development and delivery processes, improving aqueous solubility and slow dissolution of BCS Class II and Class IV drugs have been investigated extensively. Various techniques have been used in attempt to improve solubility and dissolution rates of poorly water soluble drugs which formulations, melt granulation, direct compaction, solvent evaporation, coprecipitation, adsorption, ordered mixing, Sciences, ML Sukhadia University, Udaipur, Rajasthan, India liquisolid compacts, solvent deposition inclusion complexation and steam aided granulation. In these techniques carrier plays an important role in improving solubility and dissolution For Correspondence:

Vikas A Saharan, Assistant
enhancement in drugs. This part of this review discusses enhancement of drugs while Part II [Int J Health Res, Sept Bihani S. D. College of Technical Education, Gaganpath, Sri 2009; 2(3)] describes the role and applications of cyclodextrins, carbohydrates, hydrotropes, polyglocolized glycerides, dendrimers, acids and miscellaneous carriers in Tel: +91-154-2466777 Fax: +91-154-2466774 Keywords: Dissolution enhancement; aqueous solubility,
water soluble carriers; BCS class II, excipients. Saharan et al. Dissolution Enhancement of Drugs
Introduction
characteristics of the particles. Part I of this Nearly one-third of drugs in development are water insoluble and one-half fail in trials soluble drugs as well as role of few water kinetics [1]. These poorly water soluble drugs are allied with slow drug absorption leading dissolution enhancement. While part II [Int J to inadequate and variable bioavailability and Health Res, Sept 2009; 2(3)] describes use G.I. mucosal toxicity of drugs [2]. Poorly of cyclodextrins, carbohydrates, hydrotropes, water soluble drugs belong to BCS class II polyglocolized glycerides, dendrimers, acids and Class IV [3] group of compounds. In the process of absorption of drug from oral route dissolution is the rate limiting step for lipophilic drugs. Therefore it is necessary to Techniques for Dissolution Enhan-
enhance dissolution of these drugs to ensure maximum therapeutic utility of these drugs. Before studying the various approaches to There are several techniques reported in literature for formulation of hydrophobic understand the basic process of dissolution. Dissolution is a process by which a solid drugs with enhanced dissolution rate. These substance goes into solution. The extent to techniques are carefully selected on the basis of properties of drug, excipients and given set of conditions is referred to as the solubility of the substance in the solvent i.e. rate of solution (dissolution) and amount that Solid Dispersion
can be dissolved (solubility) are not same. The dissolution rate of a drug is directly Solid dispersion is defined as a dispersion of proportional to its solubility as per Noyes- one or more active ingredients in an inert Whitney equation and therefore solubility of a carrier or matrix at solid state prepared by the melting (fusion), solvent, or melting- determines its dissolution rate and hence its solvent method [6]. In melting method carrier absorption and bioavailability eventually [4]. is melted and drug is added with stirring and melted until homogenous melt is obtained The various properties of drug that affect which is then cooled to room temperature while in solvent method drug and carrier is solubility, particle size, polymorphism, salt dissolved in minimum amount of solvent and form, complexation, wettability, etc [5] and can be targeted to enhance dissolution of reduced pressure [7]. Solid dispersions are poorly water soluble drugs. Use of water also prepared by dissolving drug and carrier soluble excipients is common and simplest in a common solvent followed by evaporation hydrophobic drugs. These excipients namely involves use of heating and solvent action to polymers, superdisintegrants, carbohydrates, dissolve the drug and carrier in solvent surfactants hydrotropes, acids etc work in followed by evaporation of the solvent. Solid different ways to enhance water solubility of dispersion technique improves the solubility, drugs. The role of techniques of preparation of formulation is as imperative as the choice bioavailability of poorly water-soluble drugs of the carriers to enhance dissolution of crystallinity of the product and surface Saharan et al. Dissolution Enhancement of Drugs Solid inclusion complexes can be prepared dispersions can be ascribed to a number of paste. Drug is then added and kneaded for specified time. The kneaded mixture is then 2. The reduction of particle size to nearly a dried and passed through sieve if required carrier dissolves, the insoluble drug is fine particles leading to an increase in both surface area and solubilization for solution of β-CD. The system is kept under magnetic agitation with controlled process parameters and protected from the light. The formed precipitate is separated by vacuum 4. The presence of carrier may also prevent filtration and dried at room temperature in order to avoid the loss of the structure water resulting in decreased interfacial tension Drug is added in alkaline solution like sodium hydroxide, ammonium hydroxide. A solution of β- Cyclodextrin is then added to dissolve presence of carrier polymers also inhibits the joined drug. The clear solution obtained neutralized using HCl solution until reaching 5. Cosolvent effect on the drug by the water the equivalence point. At this moment, the appearance of a white precipitate could be 6. Intermolecular hydrogen bonds between appreciated, corresponding to the formation of the inclusion compound. The precipitate is then filtered and dried [16]. 7. Local solubilization effect of carrier at the Various factors affecting dissolution of drug from solid dispersion includes the method of physical mixture is introduced in a suitable preparation of the solid dispersion, amount mill like oscillatory mill and grinded for and properties of the polymer carriers, drug Inclusion Complexation
Drug is dissolved in suitable solvent and the required stoichiometric amount of carrier This is most widely used method to enhance material like β cyclodextrin is dissolved in water solubility and increase stability of hydrophobic drugs by using cyclodextrins. Saharan et al. Dissolution Enhancement of Drugs produce a clear solution, which is then spray- a reduction in particle-particle agglomeration or by reducing van der Waal’s interactions. Increase in true surface area of the ordered inherent surface roughness and porosity of Drug and cyclodextrins mixture is reacted in the microcrystalline cellulose-drug mixture microwave oven to form inclusion. It is a novel method for industrial scale preparation Lipid-based formulations
reaction time and higher yield of product [17]. Lipid-based delivery systems like emulsions, Steam-Aided Granulation
microemulsions, liposomes, microspheres, solid-lipid nanoparticles, etc have ability to Steam instead of water can be used in wet granulation because it provides a higher barriers to oral absorption and are most diffusion rate into the powder and a more successful in enhancing the bioavailability of favorable thermal balance during the drying molecules that are poorly water-soluble but step. After condensation of the steam, water highly permeable drug molecules (BCS class forms a hot thin film, requiring only a small II). Some proposed mechanisms of action of amount of extra energy for its elimination and evaporates more easily. The use of steam bioavailability of compounds include [21]: instead of liquid water in a wet granulation a) Particle size reduction to molecular size amount of water used and as a result the yielding a solid-state solution within the b) Enhanced wetting of hydrophobic solids Cogrinding / Comicronization
Cogrinding of a poorly water-soluble drug aqueous environment from oil droplets of hydroxypropyl methylcellulose (HPMC), poly vinyl alcohol (PVA) etc in the presence of d) Promotion of absorption via intrinsic lipid small amount of water is extremely effective maintenance of drug crystallinity to some extent [19]. Small particles produced by environment of the gastrointestinal tract. Melt-Granulation
enhanced dissolution rate. However, energy added to reduce particle size results in increased van der Waal’s interactions and efficiently agglomerated by the use of a electrostatic attraction between particles meltable binder which can be a molten liquid, leading to reduce effective surface area due a solid or a solid that melts during the to agglomeration thus decreasing dissolution process usually in high shear mixers, where the product temperature is raised higher than excipients like microcrystalline cellulose can the melting point of the binder either by a heating jacket or, when the impeller speed is eliminate cohesive and electrostatic forces. This approach increases apparent surface generated by the impeller blades [22]. In this technique no water or organic solvents are creating an ordered mixture, thereby causing Saharan et al. Dissolution Enhancement of Drugs needed and there is no drying step therefore the drug/polymer composition is decisive in the process is environmentally safe, less preventing phase separation during freezing, time consuming and uses less energy than allowing for the active to be molecularly dispersed with the polymer. Recrystallization of the drug is avoided by the inclusion of high glass-transition temperature (Tg) polymers solution properties, low melting point, rapid such as PVP or hypromellose (HPMC). This solidification rate, low toxicity and little cost technique is widely applicable to enhance in- [22]. The increase in dissolution rate can be ascribed to the hydrophilic character of the system due to the presence of water-soluble carriers and the fact that the drug forms Coevaporate System / Coprecipitation
Direct Compaction
maleate contain good solubility in acidic pH but in alkaline pH solubility is significantly In this process polymer like hydroxypropyl methylcellulose and drug is dry-blended, formulation containing weak base is given compressed into slugs and then milled into a orally precipitation of poorly soluble free base occurs within formulation in intestinal enhanced dissolution rate of poorly water- fluid. Precipitated drug is no longer capable soluble drugs without the use of solvent or heat addition to overcome the disadvantages decrease in bioavailability of drug. This of solid dispersion by these methods. This process is also cost effective and quicker. The compaction processes are believed to carrier with solubilizing effect in alkaline be particularly effective at enhancing the rate intestinal fluid which may operate in the microenvironment, immediately surrounding particles are maintained in direct contact with the drug particle and polymers for controlling the polymer particles during drug dissolution, the dissolution rate to formulate dosage in contrast with a physical mixture where the forms ensuring maximum bioavailability with disperse and be separated in the dissolution Ordered/Interactive Mixing
Solvent
Evaporation
by
Ultra-Rapid
Ordered mixing is described as method to Freezing (URF)
prepare ordered units in the mix such that the ordered unit will be the smallest possible contained in a polymer solution onto the identical composition to all the other ordered units in the mix. Ordered mixing yields nearly thermal conductivity (k) between 10 and 20 the perfect mix and may be obtained in a W/(m K), collecting the frozen particles and adhesion, coating and other methods [27]. conductive heat transfer, resulting in high Prerequisite for fast dissolution from an supersaturation and nucleation rates, the ordered mixture includes that the carrier URF technology has the potential to create particle should dissolve rapidly, delivering a fine particulate suspension of drug particles properties, similar to those produced by [28]. Higher concentration of drug shows other rapid freezing technologies. As in other reduced dissolution rates particularly at freezing technologies, the rapid freezing of Saharan et al. Dissolution Enhancement of Drugs because high concentration of drug forms agglomerates rather than discrete particles sieve. The Increase in the dissolution rate is with resulting decreased surface area and ascribed to the reduced particle size of the thicker diffusional layers causing reduction in drug deposited on the carrier and enhanced dissolution rates [29]. In an ordered powder wettability of the particles brought about by mix fine drug particles are distributed fairly evenly on coarse carrier particles. The drug powder is therefore deagglomerated in the Carriers for Dissolution Enhance-
dry state. This may be used to increase the dissolution rate of drug powders because a larger contact surface area is exposed to the Carriers, which are soluble and dissolve in water at a fast rate, are widely used in Adsorption of Drugs onto High Surface
dissolution of drugs. The carriers which have Area Carriers
been reported in literature are presented in Table 1 and are described in detail under carriers having large surface area (like crosslinked polyvinylpyrrolidone, Kollidone) Polymers
from solutions of the drug in appropriate solvents like methanol, polyethylene glycol, Polymers like polyethylene glycols (PEGs), and 2-pyrrolidone. The dissolution rate of drug increases due to increase in surface area and drug particles have good wettability polyvinylpyrrolidone (PVP) etc when used in due to the surrounding solubilising materials optimum concentration lead to increase in dissolution rate due to reduction in particle size, solubilization effect of the carrier, Liquisolid Compacts
formation of hydrogen bonds between drug Liquid Compacts are compressible powdered and carrier (Table 2). When polymers are “liquisolid medication” implies oily liquid decrease dissolution rate due to leaching out drugs and solutions or suspensions of water- of the carrier during dissolution which might form a concentrated layer of solution around the drug particles and the migration of the released drug particles to the bulk of the converted into a dry, non-adherent, free Solid dispersions (SDs) of glyburide were excipients such as the carrier and coating material. Surfactants like tweens are used to improve aqueous solubility of poorly soluble selected solid dispersions were lyophilized. Solvent Deposition / Evaporation
In this technique drug is dissolved in a glyburide/PEG 4000, 1:10, showed an 8-fold solvent like methylene chloride to produce a and dispersion containing 6 parts of PEG clear solution. The carrier is then dispersed mixture show 12-fold increase as compared in the solution by stirring and the solvent is removed by evaporation under temperature dispersions further supplement dissolution and pressure. The resultant mass is then Saharan et al. Dissolution Enhancement of Drugs Table 1: Classification of carriers enhancing dissolution of drugs
Polyvinylpyrrolidone, Polyvinylpolypyrrolidone, Polyvinyl alcohol, Polyethylene glycols, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, Poly (2-hydroxyethylmethacrylate), Methacrylic copolymers (Eudragit® S100 sodium salts and Eudragit® L100 sodium salts) Sodium starch glycolate, Croscarmellose sodium, Cross-linked polyvinylpyrrolidone, Cross-linked alginic acid, Gellan gum, Xanthan gum, Calcium silicate β-Cyclodextrins, Hydroxypropyl-β-cyclodextrins Lactose, Soluble starch, Sorbitol, Mannitol, β-(1-4)-2-amino-2-deoxy-D-glucose (Chitosan), Maltose, Galactose, Xylitol, Galactomannan, British gum, Amylodextrin Poloxamers (Lutrol® F 127, Lutrol® F 68), Polyglycolized glyceride (Labrasol), Polyoxyethylene sorbitan monoesters (Tweens), Sorbitan esters (Spans), Polyoxyethylene stearates, Poly (beta-benzyl-L-aspartate) -b- poly (ethylene oxide), Poly (caprolactone) -b- poly (ethylene oxide) Urea, Nicotinamide, Sodium benzoate, Sodium salicylate, Sodium acetate, Sodium-o-hydroxy benzoate, Sodium-p-hydroxy benzoate, Sodium citrate Gelucire 44/14, Gelucire 50/13, Gelucire 62/05 Citric acid, Succinic acid, Phosphoric acid Microcrystalline cellulose, Dicalcium phosphate, Silica gel, Sodium chloride, Skimmed milk due to increase in surface area and hence PVP ratio. The drug:PVP in 1:4 ratio, solid dispersion gave highest dissolution rate of about a 38-fold higher than that of pure drug [12]. Solid dispersions of norfloxacin with PEG 6000 in weight ratios of 10:90, 20:80, 30:70 and 50:50 were prepared by fusion method. Solubility studies revealed no significant fusion method involving heating a physical increase in solubility of norfloxacin on addition of PEG. Dissolution studies showed 4000 or PEG 6000 in 1:2, 1:4, 1:6 and 1:8 maximum dissolution rate of drug with PEG drug/carrier ratios, to the liquid state. Dissolution studies suggested that the dissolution of carbamazepine from the solid establishing the effect and importance of optimum weight fraction of polymer [33]. molecular weight nor the weight fraction of Solid dispersions of piroxicam were prepared solid dispersion may be ascribed to complex using polyvinylpyrrolidone K-30 in 1:0.5, 1:1, 1:2, 1:3, 1:5 and 1:6 ratio of drug to polymer by solvent method. The dissolution of drug in solid dispersion was dependent on drug to dispersion with carbamazepine crystalling in Saharan et al. Dissolution Enhancement of Drugs Table 2: Polymers and techniques employed for enhancing dissolution of poorly water soluble drugs
Increase in surface area and hence surface free energy resulting in an increase in the dissolution presence of intermolecular hydrogen bonds between piroxicam and PVP carbamazepine and PEGs during melting and a polymorphic change during the preparation of solid dispersion, with carbamazepine crystalling in a metastable form of higher dissolution rate solubilization effect of carrier at the diffusion layer, formation of amorphous phase of piroxicam and particle size reduction resulted from interaction of drug and PEG 4000 Reduction of particle size of the drug and surface tension lowering effect of carriers resulting in wetting of hydrophobic roxithromycin surface enhancement of surface area and increase in drug wettability Saharan et al. Dissolution Enhancement of Drugs Table 2: Polymers and techniques employed for enhancing dissolution of poorly water soluble drugs (continued)
Increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form from the carrier, improved wetting and solubilization Formation of interstitial solid solutions Higher hydrophilic character of the system due to the presence of water-soluble carriers and part of the drug dissolved in the binder Microenvironment surfactant effect where surfactant concentration in the boundary layer surrounding the drug particles, providing a lower energy pathway for drug dissolution Increase in solubility driving force, lowering the heat of solution of the danazol, nano-structured amorphous drug domain, and improved surface area. Saharan et al. Dissolution Enhancement of Drugs a metastable form of higher dissolution rate concentration of polymers from 0.5 to 3 % polymer solution. Angle of repose and carr’s Solid dispersions of piroxicam in PEG 4000 index studies indicated fine nature and good at 1:1, 1:2 and 1:3 ratio of drug to polymer flow properties of the all formulations [10]. were prepared by fusion and solvent method with enhanced dissolution due to increased Solid dispersions of gliclazide were prepared wettability of drug, a local solubilization effect using PEG 4000 and PEG 6000 in 1:1, 1:3, of carrier at the diffusion layer, formation of and 1:5 ratio of drug to polymer by solvent amorphous phase of piroxicam and particle method using chloroform as solvent. Drug: size reduction resulted from interaction of carrier ratio of 1:5 was found to be optimum drug and PEG 4000. Storage stability studies for improving dissolution rate of gliclazide for at 25°C and 37° C for 10 weeks showed that dispersions showed faster dissolution than uptake of water during storage may occur in dispersions of albendazole were prepared piroxicam potency in piroxicam-PEG solid using PEG 6000 in 1:1, 1:3 and 1:5 ratio of Solid dispersions of flurbiprofen in PVP, improved dissolution compared to physical mixtures owing to increased surface area for ratio of drug to carrier were prepared by mass transfer, thermodynamically enhanced solvent method. Among these polymers PVP dissolution of a higher energy amorphous gave highest enhancement (19-fold) in the form from the carrier, improved wetting and dissolution rate of flurbiprofen at 9:1 drug to flurbiprofen with various polymer solutions Solid dispersions of rofecoxib with PVP, PEG was in the descending order of PVP, HPMC, PEG, and HPC at 9:1 ratio of drug to carrier. w/w were prepared by hot-melt method. The As concentration of carrier in solid dispersion solubility efficiency of polymers was in the was increased, the rate of dissolution was order of PVP >> PEG 4000 > PEG 6000 due to high amorphizing properties of PVP than aggregation of drug and carrier in solid carrier amoumt i. e. 90% and was ascribed to the formation of interstitial solid solutions prepared using PEG 6000 by fusion method. Solid molecular dispersion of diclofenac dissolution of glibenclamide compared with sodium, naproxen and piroxicam using Poly marketed daonil(R) tablets (Hoechst) due to improved wettability and dispersibility of drug hydrogel as carrier were prepared by solvent from solid dispersion [36]. Solid dispersions of roxithromycin were prepared using PEG, HPMC and HPC in 1:1, 1:3, and 1:5 ratio of naproxen, and 100% acetone for piroxicam. drug to polymer by coprecipitate method. The results showed threshold drug loading The dissolution rate of roxithromycin solid level of about 30% in these solid dispersions, dipersions was in the descending order of Solubility of roxithromycin was directly polymer improves the compatibility between Saharan et al. Dissolution Enhancement of Drugs drug and polymer. Stability studies under varying conditions of humidity (22-92 RH %) showed transition from clear sample to an opaque one on increasing humidity due to granulation technique using PEG 4000 as a melt binder without using solvents or water. Solid-state analysis indicated only a limited reduction of the crystallinity of the drug and no changes in its polymeric form. Granulates showed a significant improvement of in vitro Coground mixtures of nifedipine, griseofulvin, intragranular addition of crospovidone (PVP- dispersing drug in the fused PEG 6000 and CL) was found to be necessary to produce tablets with a satisfactory disintegration time temperature, the solidified mass was ground using a ball mill. Then solvent like water, Granules of griseofulvin (2.5, 5.0%) were added to observe the effect of solvents and prepared by melt granulation technique using further ground and dried to remove solvent. The resultant mass was lightly pulverized to Dissolution rate of all prepared granules was participate in the solubility enhancement and physical mixtures. Granules having PEG as process through the functional groups in a small amount of water added (highly polar environment). Solubility also increased in the containing Gelucire 44/14 as binder showed presence of organic solvents suggesting that a significant dissolution enhancement as the pulverizing effect for drugs like nifedipine compared to drug but slightly enhancement also promote the drug- polymer interactions compared to physical mixtures. The increase in dissolution rate was ascribed to the highly polar environment provided by water-soluble Lipid based formulations of piroxicam were carriers, part of the drug dissolved in the prepared using 1,2-dimyristoyl-sn-glycero-3- binder and formation of monotectic mixture phosphatidylcholine (DMPC) phospholipids alone in 1:1and 2:1 ratio of drug:DMPC and ratio. Dissolution studies showed highest carbamazepine at a 1:1 polymer:drug weight increase in drug release from combination of lipid with PEG as compared to lipid alone due to solubilizing effect of PEG on the drug and E5LV) and methyl cellulose polymers by thus enhancing the dissolution rate. Storage slugging and roller compaction method. The stability studies at 4°, 25° and 60°C revealed stability of at least 6 months but beyond this produced comparable rate and extent of drug decrease in dissolution rates for formulations dissolution. This method require no solvent containing PEG 4600 due to formation of a or heat for formulation and is cost effective, crystalline mass upon storage for extended quicker, readily scalable at industrial scale period. Stabilizers like polyvinyl alcohols can be added to increase storage stability of all Saharan et al. Dissolution Enhancement of Drugs Micronized danazol powders were prepared drug solubility by two times while maintaining by ultra rapid freezing using polyvinylpyrro- the desirable mucoadhesive properties [39]. lidone K-15 at a 1:2 ratio and 0.55% total solid in either tert-butanol heated to 313 K or Superdisintegrants
acetonitrile solvent at room temperature with Dissolution of poorly water soluble drugs can different solvents markly alters surface produced by acetonitrile were spherical and glycolate, croscarmellose sodium, crospovi- uniform in size as a result of the more rapid and uniform cooling of the droplets relative to crosslinked alginic acid etc [40]. Some of the tert-butanol. This process is viable and recent studies utilizing superdisintegrants are robust for producing high surface area nano- structured powders for enhancing dissolution Sodium starch glycolate swells 7- to 12-fold in less than 30 sec. uniformly in all three Coevaporates of prochlorperazine maleate dimensions while croscarmellose swells 4- to 8-fold in less than 10 sec. in two dimensions leaving fibre length similar. This indicates methylcellulose phthalate as a carrier for that rate, force, and extent of swelling have solubilization of drug in alkaline medium and an important role in disintegrants that work ethyl cellulose, hydroxypropyl cellulose for by swelling. Cross-linked PVP swells little controlling the dissolution rates of weak (due to absence of cationogenic groups in the molecule) but returns to its original Wicking or capillary action also is postulated to be a major factor in the ability of cross- Fast-dissolving mucoadhesive microparticles linked PVP to work as superdisintegrant [41]. for sublingual administration could be a suitable alternative to fast-dissolving tablets extensive swelling properties for faster because the sublingual absorption can be disintegration. Calcium silicate is a highly residence time on the mucosa and reducing wicking action. Cross-linked alginic acid is a hydrophilic colloidal substance with high sorption capacity and acts by swelling or copolymers, namely viz. Eudragit® L sodium salt and Eudragit® S sodium salt, were used as effective carriers for the preparation of the Carrier particles of size from 50 to 1000 microparticles in ratio ranging from 15/85 to microns with cross-linked sodium (Ac-Di-Sol) 85/15% (m/m) by spray drying. Their intrinsic disintegrant in an optimum amount of 5 to dissolution rates are faster than those of liquid (ethanol) which did not dissolved the disintegrant or caused the disintegrant to swell [42]. These carrier particles were mixed microparticles which was anticipated due to with micronized oxazepam for 50 hours to H-bond between the NH group of piroxicam obtain ordered mixture with surface area and a CO group of the copolymers. The best ratios of 0.08, 0.57 and 1.5. With addition of 1% sodium lauryl sulphate in finely dispersed Eudragit® L sodium salt in the ratio 70/30% substance in the carrier, the dissolution rate Saharan et al. Dissolution Enhancement of Drugs
Table 3: Superdisintegrants and techniques employed for enhancing dissolution of poorly water soluble drugs
Higher surface area of the carrier and capillary Swelling action of croscarmellose sodium Swelling action of sodium starch glycolate, Faster dissolution from amorphous ibuprofen, drug deposition on carrier surfaces and polymer swelling Swelling action of sodium starch glycolate, Swelling action of sodium starch glycolate, Saharan et al. Dissolution Enhancement of Drugs was independent of whether or not the water solvent contains an additional surfactant [43] ibuprofen and cross-linked polyvinylpyrroli- done were prepared as physical mixes, and markedly that about 90% of the composition drug was loaded onto the polymer by hot mix has passed into solution after two minutes. and solvent deposition method. Increased dissolution rate of ibuprofen were achieved Improvement of dissolution rate of nifedipine by solid deposition on high percentages of deposition, hot mixes, physical mixes. The sodium starch glycolate and croscarmellose increased dissolution rate could be ascribed to a combination of faster dissolution from deagglomeration of the micronized drug by the superdisintegrant particles and solid carrier surfaces and polymer swelling [48]. swelling superdisintegrants which act as a Tablets of aspirin were prepared by direct carrier. As an effect of swelling of the compression technique using sodium starch superdisintegrants, the ‘wetted’ surface of crospovidone as superdisintegrants. It was wettability and dispersibility of the particulate comparable for tablets formulated with 1% croscarmellose sodium, 2% crospovidone, or Coprecipitates of furosemide-crospovidone dissolution of aspirin from these tablets methanol with enhanced dissolution rate due varied in the following descending order to association between the functional group despite the closeness of their disintegration times: croscarmellose sodium, sodium starch probably between imino and sulfonylamide hydrochlorthiazide tablets were prepared by group of furosemide and carboxyl group of starch glycolate, croscarmellose sodium as superdisintegrants with enhanced dissolution Dispersible tablets of flurbiprofen were microcrystalline cellulose and sodium starch glycolate disintegrants alone and in different dissolved in methanol, polyethylene glycol, 2-pyrrolidone and adsorbed onto the surface (Kallidone). The solvent binding capacities 4000, 2-pyrrolidone. Improved dissolution glycolate disintegrated rapidly and gave faster dissolution of flurbiprofen [46]. surface area of the carrier [30]. Similarly increase in dissolution rate of naproxen by starch glycolate (Primogel), Ac-Di-Sol, and prepared by solvent evaporation method with enhanced dissolution of tenoxicam. Kollidon sodium, and crospovidone as disintegrants in 2% w/w concentration were prepared by wet granulation technique using intragranular and extragranular methods. Disintegration Saharan et al. Dissolution Enhancement of Drugs and dissolution studies revealed intragra- nular method of application of disintegrants more suitable which help the tablet to burst poloxamer 407 as surfactant at 1:1, 1:3, 1:5 into smaller particles as well as it may help to dissolve the drug faster. Croscarmellose sodium incorporated intragranular method gave better results than extragranular method as well as better than sodium starch solubility enhancement due to surface active property and critical micellar concentration. extragranular and intragranular methods for The albendazole-poloxamer melt (1:5 ratio) showed 16.1 fold dissolution rate and 9.4 fold in dissolution efficiency as compared to that of pure drug due to solubilization effect superdisintegrants is an easy alternate to enhance dissolution of poorly water soluble Solid dispersions of rofecoxib were prepared excipient and changing the methodology of (Lutrol® F127 and Lutrol® F68) in 50%, 75% solubility of system was observed due to superdisintegrants is its cost but overall cost micellar solubilization and/or reduction of of formulation is less as compared to opting activity coefficient of the drug through specific measure to enhance dissolution. reduction of hydrophobic interaction(s) and Surfactants
Several liquisolid compacts were prepared by dispersing piroxicam in tween 80 as liquid to prepare liquid medication of the different drug concentrations with different ratios of oxide)-poly (ethylene oxide) – poly (propy- drug:tween 80 ranging from 1:1 to 1:9 using binary mixture of microcrystalline cellulose (carrier powder)-silica (coating material) and aspartate) -b- poly (ethylene oxide), Poly (caprolactone) -b- poly (ethylene oxide) etc enhanced dissolution rate because drug is already in solution in tween 80 and same time drug is carried by powder particles of drug solubility by using the amphiphilic the liquisolid vehicle. Thus, its release is surfactants is due to lowering surface tension accelerated due to increased wettability and between drug and solvent, improvement of surface availability to the dissolution medium solubilization of the drugs. Micelles are Conclusion
macromolecules where unimers are held by non-covalent interactions. The core of the Numerous technological advancements have been introduced for dissolution enhancement corona/shell allows for their suspension in of poorly water soluble drugs. Most of these Saharan et al. Dissolution Enhancement of Drugs Table 4: Surfactants and techniques employed for enhancing dissolution of poorly water soluble drugs
carrier, decreased crystallinity of the product surface availability of the drug to the dissolution medium modeling of drug release of a poorly water-soluble properties like solubility, particle size, crystal drug using water-soluble carriers. Eur J Pharm habit etc. Some of the carriers are especially Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug dispersed in them or by size reduction (co- classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res micronization). Complexation of drug with suitable carrier also alters the solubility and dissolution characteristics due to extremely Biopharmaceutical classification system. Indian high aqueous solubility of the carrier. The solubility and dissolution rate improvements Jaiswal SB, Brahmankar DM. Biopharmaceutics are also expected due to co-solvency effect and pharmacokinetics. A Treatise; 1999; 25:165. and solubilisation effect of carriers in Vadnere MK. Coprecipitates and melts. In: aqueous vehicles. In a nutshell it could be Swarbrick J, Boylan, JC, editors. Encyclopaedia of pharmaceutical technology 2nd ed. New York, USA: Marcel Dekker, Inc.; 2002. 641-647 p. modifications are an important tool to a Pan RN, Chen JH, Chen RRL. Enhancement of formulation scientist in designing immediate dissolution and bioavailability of piroxicam in solid and fast release drug delivery systems. The article continues as Part II [Int J Health Res, Reddy SJ, Gudsoorkar VR. Solid dispersions of applications of cyclodextrins, carbohydrates, gliclazide. Indian Pharmacist Aug. 2005; IV:82-84. Betageri GV, Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and 10. Patro S, Choudhary AA. Effect of some hydrophilic polymers on dissolution rate of roxithromycin. References
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