Solvent Systems And Their

Solvent Systems and Their Selection in Pharmaceuticals and Biopharmaceutics

Prof. Agnimitra Dinda School of Pharmaceutical Sciences India

Introduction: • Solvent systems are integral to drug development and pharmaceutical technology. • This single topic encompasses numerous allied subjects running the gamut from recrystallization solvents to biorelevant media. • The goal of this contribution to the Pharmaceutical Area is to make effective and informed decisions concerning the use of solvents and solvent systems.

Use of Solvent: • The use of solvents to effect drug substance crystallization and polymorph selection. • The use of solvent systems in high throughput screening and early discovery. • Solvent use in preformulation. • The use of solvents in biorelevant dissolution and permeation experiments. • Solvents and their use as toxicology vehicles, solubilizing media and excipients in oral and parenteral formulation development specialized vehicles for protein formulation, and solvent systems for topical and pulmonary drug administration.

Principles of Solubility: • Solubility is defined as the maximum quantity of a substance that can be completely dissolved in a given amount of solvent, and represents a fundamental concept in fields of research such as chemistry, physics, food science, pharmaceutical, and biological sciences. • The solubility of a substance becomes especially important in the pharmaceutical field because it often represents a major factor that controls the bioavailability of a drug substance.

• Moreover, solubility and solubility-related properties can also provide important information regarding the structure of drug substances, and in their range of possible intermolecular interactions. • For these reasons, a comprehensive knowledge of solubility phenomena permits pharmaceutical scientists to develop an optimal understanding of a drug substance, to determine the ultimate form of the drug substance, and to yield information essential to the development and processing of its dosage forms.

Thermodynamics of Solubility: • The equilibrium solubility of a substance is defined as the concentration of solute in its saturated solution, where the saturated solution exists in a state of equilibrium with pure solid solute. • For the particular system of a saturated solution, the dissolved solute in the solution and the undissolved solute of the solid phase are in a state of dynamic equilibrium. Under those conditions, the rate of dissolution must equal the rate of precipitation and hence the concentration of the solute in the solution remains constant (Temp. Const.).

Dissolution Phenomena: Kinetics of Solubility

• Systemic absorption of a drug substance from a particulate form takes place after the compound enters the dissolved state. If the dissolution rate of the substance is less than the diffusion rate to the site of absorption and the absorption rate itself, then the dissolution process will be the rate-determining step. This situation is characteristic of drug substances that have low degrees of aqueous solubility, and therefore low dissolution rates.

• Noyes and Whitney (1897) developed an equation based on Fick’s second law of diffusion to describe dissolution within the scope of their model, and report the relation: dC ---dt

DS = ---- (Cs − C) h

Hixson and Crowell model: • Hixson-Crowell model is applied to micronized particles, for which the thickness of the aqueous diffusion layer around the dissolving particles is comparable to or larger than the radius of the particle, the change in particle radius with time is given by:

r2 = r02

2DGst - ---------ρ

• r0 is the initial radius of the particle, r is the radius of the particle at time equal to t, D is the diffusion coefficient of the molecules dissolving from the particle, CS is the equilibrium solubility of the substance, and ρ is the density of the solution.

Ionic Equilibria and the pH Dependence of Solubility: • Many drug substances can be classified as being either acids or bases in that they possess the ability to react with other acids or bases that are stronger than themselves. • As such, they would also possess the ability to exist as ionic species under certain conditions. • The state of ionization of a substance will often profoundly affect its degree of aqueous solubility, as evidenced by the high solubility of sodium benzoate as opposed to the low solubility of benzoic acid. The utility of salt forms as active pharmaceutical ingredients is well known, and represents one of the means to increase the degree of solubility of an otherwise intractable substance.

Ionic Solubility Depends on: • Activity, Activity Coefficients, and the Equilibrium Constant • Equilibria of Weak Acids and Bases • Ionic Equilibria of Acidic and Basic Substances • Ionic Equilibria of Buffer Systems • pH Dependence of Aqueous Solubility

Solubility in Preformulation: • Solubility is one of the most important physicochemical properties studied during pharmaceutical preformulation. • For liquid dosage form development, accurate solubility data are essential to ensure the robustness of the finished product. • For solid dosage forms, solubility data are important in determining if an adequate amount of drug is available for absorption in vivo. • If a compound has a low aqueous solubility, it may be subject to dissolution rate-limited or solubilitylimited absorption within the gastrointestinal (GI) residence time

Solubility in MAD: • Solubility data are also used to estimate the maximum absorbable dose (MAD) • MAD is a conceptual tool that relates the solubility requirement for oral absorption to the dose, permeability and GI volume and transit time. •

MAD (mg) = S (mg/mL) × Ka (1/min) × SIWV (mL) × SITT (min)

• where S is solubility at pH 6.5 reflecting typical small intestine condition; Ka is the trans-intestinal absorption rate constant determined by a rat intestinal perfusion experiment; SIWV is the small intestine water volume, generally considered to be 250 mL; and SITT is the small intestine transit time, typically about 270 min.

Solubility Issues in Early Discovery and HTS (high throughput screening):

• Drug discovery programs begin with target identification and validation for diseases with unmet medical needs. • Compounds that are used in HTS, bioassays and ADME screening are typically dissolved and stored in DMSO at a concentration of 10– 30 mM.

Drug Characteristics into Biorelevant Dissolution Media • Oral administration is the most convenient way to deliver drugs, and therefore the most preferred. • When moving from the stomach through the pylorus into the small intestine, the drug will meet a rapidly changing environment including bile and pancreatic secretions which will introduce different enzymes and surface active bile components, and increase in pH from acidic to neutral. • An increasing problem for the pharmaceutical industry, partly arising from the introduction of high throughput screening, is the discovery of highly hydrophobic active pharmaceutical candidates with low water solubility.

pH ranges in GIT: • The Stomach - pH ranges between 1.5 and 2.9 • The Upper Small Intestine - pH values between 6 and 7.1

Biorelevant Dissolution Media: • Which media, or combination of media, to choose, will depend on the physicochemical characteristics of the compound, and, when relevant, also on the type of formulations involved. • The simplest dissolution media simulating gastric fluids is the USP test fluid without pepsin, consisting essentially of 0.1 N HCl

Solvent Systems for Permeability Screening • To improve the performance of in vitro absorption models, a multitude of approaches have been proposed to overcome the limitations associated with classical experimental conditions. • e.g. Solubility Enhancers-DMSO

Solubilizing Vehicles for Oral Formulation Development • Drug molecules that are poorly water-soluble can be difficult to effectively administer in vivo due to solubility limitations. • There is a wide selection of solubilizing excipients that are generally regarded as safe that can be judicially used to safely and effectively administer drugs with a wide variety of physiochemical properties and chemical structures. e.g. Propylene glycol (PG), medium-chaintriglyceride, or a mixture such as PEG 400/PG, PEG 400/d-α-tocopherol polyethylene glycol 1000 succinate (TPGS),

Solubilizing Excipients and Mixtures: • Water-Soluble Organic Solvents-polyethylene glycol 400 (PEG 400), ethanol. • Surfactants-Polyoxyl 35 castor oil (Cremophor EL)Polyoxyl 40 hydrogenated castor oil Cremophor RH40), Polyoxyl 60 hydrogenated castor oil (Cremophor RH60), Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80) • Cyclodextrins- cyclic (α-1,4)-linked oligosaccharides of α-D-glucopyranose

Pharmaceutical Solvents as Vehicles for Topical Dosage Forms • The selection of a vehicle can dramatically affect delivery and consequently efficacy of topical preparations. • In terms of transdermal delivery, where delivering therapeutic agents for systemic effects is desired, solvents and co-solvent systems are widely used to improve both the amount and range of drugs that can be administered at therapeutic levels through the skin.

General Principles for Solvent Selection: • Thermodynamics • Vehicle Effects on the Skin • Biological Factors

Solvents Used As Vehicles: • • • • • • • •

Water Alcohols Ethanol Isopropyl alcohol Glycols Paraffins Oleic acid Isopropyl myristate

Conclusion: Solvent systems are integral to drug development and pharmaceutical technology. Above discussion have been designed to cover the theoretical background of solubility, the effect of ionic equilibria and pH on solubilization, the use of solvent systems in high throughput screening and early discovery, solvent use in preformulation, the use of solvents in biorelevant dissolution and permeation experiments and in various formulations. In addition, trends in the use of solvent systems and a balance of current views make this monograph useful.