Various approaches to improve dissolution of poorly soluble

Various approaches to improve dissolution of poorly soluble drugs : 

Various approaches to improve dissolution of poorly soluble drugs By: Sai Kishan Dept: Industrial pharmacy

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INTRODUCTION : Dissolution monitors the rate at which a solid or semisolid pharmaceutical dosage form releases the active ingredient(s) into the liquid medium under standardized conditions of liquid/solid interface , temperature, and media composition . Dissolution tests are defined “category III” by USP. Dissolution testing is primarily used in industry as a quality control tool to monitor the formulation and manufacturing process of the dosage form .

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Definition: Dissolution is the process by which a solid or liquid forms a homogeneous mixture with a solvent (solution). This can be explained as a breakdown of the crystal lattice into individual ions, atoms or molecules and their transport into the solvent. The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution.

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Dissolution theories: Dissolution of a solute is a multistep process involving heterogeneous reactions/interactions between the phases of the solute-solute, solute-solvent, solvent-solvent, and at the solute-solvent interface. As one of the most commonly known mass transfer rate processes, the component heterogeneous reactions may broadly be categorized into (i) diffusion or convective transport of the solute from the interface to the bulk phase; and (ii) the rate of solute liberation and transport from and across the interfacial boundaries. Different theories developed to define dissolution are:

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Fick’s First Law Jix = -Di (aci/ax) Considers diffusion only under steady-state conditions. 2. Fick’s Second Law ac/at = D (a2c/ax2) Used when drug concentration decreases with time; hence, considers non-steady state conditions. 3. Noyes and Whitney d c/dt = K (cs - ct) Description of drug dissolution based on constant surface area. 4. Brunner and Tolloczko d c/dt = kS (cs - ct) Manipulation of Noyes-Whitney’s eq 3 by incorporation of surface area term S. Proposed the formation of a stagnant layer around the dissolving particle, a layer through which solute diffuses through into the bulk.

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5. Hixson and Crowell Cube Root W o 1/3 - w 1/3 = (4πp ᶯ /3) 1/3 ( Dc s/ h p) t (or) W o 1/3 - w 1/3 =kt Originally developed for single particles but has been extended to use in multiparticulate systems. 6. surface renewal vd c /d t = d W /d t = S ( ƔD ) 1/2 ( c s - c t) Assumes solid-solution equilibrium is achieved at the interface and that mass transport is the rate-limiting step in the dissolution process. 7. limited salvation G = k I( c s - ct ) An intermediate drug concentration less than saturation may exist at the interfacial barrier between the solid surface and solvent. Different faces of a crystal may have different interfacial barriers and therefore make different contributions to the dissolution process.

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Where, D i: diffusion coefficient; ac i/ ax : concentration gradient; ac / at or d c /d t : drug dissolution rate; K : first-order dissolution constant; c s: equilibrium drug concentration; ct : drug concentration at time t ; k : dissolution constant; S : surface area; v : volume of dissolution medium; h : thickness of stagnant layer; w 0: initial powder weight; w : powder weight at time t ; p: particle density; ᶯ : viscosity; h : thickness of diffusion layer; Ɣ : interfacial tension; G : dissolution rate per unit area; k I: effective interfacial transport constant.

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Biopharmaceutical classification system (BCS) classifies an NCE into four major categories. 40% of the NCE's fall in class II and class IV. Formulating such a molecule into a suitable oral dosage form for a desired therapeutic response poses a challenge to the formulation scientist. Techniques: There are a number of methods to improve the dissolution/bioavailability of poorly soluble drugs including:

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Pro-drug approach Salt synthesis Particle size reduction Complexation with cyclodextrins Change in physical form Solid dispersions Spray drying Hot-melt extrusion. Solid dispersion : various strategies include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology. Fusion method: This process employs melting of the mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after fusion, the sample are poured onto a metallic plate which is kept on

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ice bath. Decomposition should be avoided and is affected by fusion time and rate of cooling . Ex: SD of troglitazone- polyvinyl pyrrolidone (PVP) k 30 . The fusion process does not require an organic solvent . Solvent evaporation method: The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. Large volumes of solvents are generally required which can give rise to toxicological problems. SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected.

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Melt agglomeration process: This technique has been used to prepare SD where the binder acts as a carrier. Binder (carrier), drug and excipients are heated to temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer . Extruding method: Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die. This method has been used successfully to prepare SD(s) of Itraconazole and hydroxypropylmethylecellulose (HPMC) ,

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Melt agglomeration process

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Extruding apparatus

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Indomethacin/lacidipine/nefidipine/ piroxicam/ tolbutamide and polyvinylpyrrolidone (PVP) 52 , Itraconazole and HPMC 2910/ Eudragit E 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64. Spray drying: It is an method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process, resulting solid particles. The process allows production of fine, dust free powder. SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. The dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane.

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Dual spray dryer

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Use of surfactants : Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have been used for preparation of solid dispersions. Recently a new class of surfactant known as Gelucires was introduced. Gelucire is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol (PEG) . Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point, while 14 and 13 represent HLB values of gelucire respectively . Ex: Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000- gelucire 44/14 .

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Salt formation: This is the most widely used approach to increase solubility of weakly acidic or basic poorly soluble drugs. If the poorly soluble drug has ionisable groups, then it is very likely that it will form a salt. The solubility of salt is typically based on the counter ion. Selection of salt is based on many parameters such as solubility, hygroscopicity and stability of the physical form. The most important requirement is that the counter ion should be FDA approved.

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