Dissolution Analysis PDF

Dissolution Yussif Saaka BPharm, MSc., Ph.D., MPSGH Department of Pharmaceutics [email protected] SOPH 331 PHARMACEUTICAL TECHNOLOGY II UNIVERSITY OF HEALTH AND ALLIED SCIENCES...

Dissolution Yussif Saaka BPharm, MSc., Ph.D., MPSGH Department of Pharmaceutics [email protected] SOPH 331 PHARMACEUTICAL TECHNOLOGY II UNIVERSITY OF HEALTH AND ALLIED SCIENCES School of Pharmacy  Objectives To understand: o the principles of dissolution o drug-release kinetics o the Noyes-Whitney equation ▪ factors affecting dissolution rate o dissolution testing ▪ USP apparatuses ▪ dosage form-specific testing 2  Introduction Dissolution: o the process by which molecules of a solid substance (the solid phase) form a one-phase, homogeneous, molecular mixture with a solvent. o A scheme was proposed by Wagner for the processes involved in the dissolution of solid dosage forms. Solid dosage form Granules or aggregates Fine particles Disintegration Deaggregation Dissolution Drug in solution in vitro/ in vivo Drug in blood, other fluids and tissues 3  Introduction Wagner’s scheme was modified by Carstensen o by incorporating other factors that precede the dissolution process of solid dosage forms. o Carstensen proposed the following scheme: ▪ Initial mechanical lag ▪ Wetting of the dosage form ▪ Penetration of the dissolution medium into the dosage form ▪ Disintegration ▪ Deaggregation of the dosage form and dislodgement of the granules ▪ Dissolution and occlusion of some particles of the drug 4  Introduction Carstensen explained that: o the wetting of the solid dosage form surface controls the liquid access to the solid surface and, many times, is the limiting factor in the dissolution process. o Remember the relationship between wetting, interfacial tension and contact angles! From the schemes above, o It is apparent that the rate of drug dissolution can become the only rate-limiting step before it appears in the blood. o However, when the dosage form is placed into the GIT in solid form, there are two possible rate-limiting steps. 5  Introduction o Possible rate-limiting steps. ▪ The solid must first dissolve, and the drug in solution must then pass through the gastrointestinal (GI) membrane. ❑ Freely water-soluble drugs tend to dissolve rapidly, making the passive diffusion of the drug or the active transport of the drug rate- limiting step for absorption through the GI membrane. ▪ The rate of absorption of poorly water-soluble drugs will be limited by the rate of dissolution of the undissolved drug or disintegration of dosage form. Drug release: o the process by which a drug leaves a drug product and is subjected to absorption, distribution, metabolism and excretion. 6  Drug Release Kinetics Zero-order kinetics: o constant drug release from a drug delivery device (i.e. amount of drug released per unit of time is constant). o e.g. oral osmotic tablets, transdermal systems, matrix tablets with low soluble drugs. 𝐶 = 𝐶0 + 𝑘𝑡 𝐶 = amount of drug released in time, 𝑡 𝐶0 = initial amount of drug in solution (i.e. time, 𝑡 = 0) 𝑘 = zero order release rate constant 7  Drug Release Kinetics First-order kinetics: o rate of drug release is dependent on its concentration (i.e. amount of drug released per unit time varies). o e.g. water soluble drugs in porous matrices. 𝐶 𝐶 = 𝐶0 𝑒 −𝑘𝑡 or ln 𝐶0 = 𝑘𝑡 𝐶 = amount of drug released in time, 𝑡 𝐶0 = initial amount of drug in solution (i.e. time, 𝑡 = 0) 𝑘 = first-order release rate constant 8  Noyes-Whitney Equation The rate at which a solid dissolves when in contact with a solvent is expressed by the Noyes-Whitney equation: 𝑑𝑀 𝐷𝑆 = 𝐶𝑠 − 𝐶 𝑑𝑡 ℎ 𝑀 = the mass of the solute that goes into solution in time 𝑡 𝑑𝑀 = the dissolution rate 𝑑𝑡 𝑆 = the surface area of the solid available to interact with the solvent 𝐷 = the diffusion coefficient of the solute in the solvent ℎ = thickness of the diffusion layer 𝐶𝑠 = the saturation solubility of the solute in the given solvent 𝐶 = the concentration of the solute in bulk solution 9  Noyes-Whitney Equation The surface of the solid exposed to an aqueous medium has: o an aqueous diffusion layer = a stagnant liquid film on the solid surface. Molecules of the solute dissolve in the liquid film and achieve a saturation concentration (𝐶𝑠 ) at the interface of the solid and the liquid film. Solid Diffusion Bulk layer solution 𝐶𝑠 𝐶 h 10  Noyes-Whitney Equation o These molecules then diffuse through the liquid film toward the bulk solution, where the drug has a lower concentration. o The driving force for this step is the concentration gradient across the diffusion layer. o If the concentration of the solute in the bulk solution is significantly lower than the saturation solubility of the drug (say 𝐶 < 0.15 𝐶𝑠 , and 𝐶𝑠 − 𝐶 ≈ 𝐶𝑠 ), then sink conditions apply. o The Noyes-Whitney equation for sink conditions can be expressed as follows: 𝑑𝑀 𝐷𝑆𝐶𝑠 = 𝑑𝑡 ℎ o Find out: ▪ The drug release kinetics of sink and non-sink conditions (i.e. zero- or first- order kinetics). ▪ Are there similarities between the expressions for the rate of diffusion through a membrane (Fick’s law) and the rate of dissolution from a solid (Noyes- Whitney equation)? 11  Noyes-Whitney Equation Surface area, 𝑆: o dissolution rate of a solid in contact with the solvent depends on the total surface available for interaction with the solvent. o Particle size reduction: ▪ results in ↑ 𝑆 = ↑ dissolution rate of poorly soluble drugs. o Tablets for immediate drug release: o often break apart by disintegration into smaller aggregates (granules) and then by de-aggregation to yield the individual particles = ↑ in effective surface area. o If the tablet does not disintegrate, dissolution and erosion occur only on the tablet surface as the tablet geometry shrinks. 12  Noyes-Whitney Equation Saturation solubility of the drug, 𝐶𝑠 : o is the concentration of the drug achieved at the interface of the solid surface and the aqueous diffusion layer. o Metastable solid forms of a drug (e.g. amorphous) = ↑ free energy = ↑ thermodynamic solubility than that of a stable crystalline form of the same drug. ▪ This causes a higher concentration gradient in the diffusion layer to be achieved = ↑ dissolution rate. ▪ Use of stabilized amorphous forms of drugs is a widely reported approach for improving the bioavailability of poorly water-soluble drugs 13  Noyes-Whitney Equation Saturation solubility of the drug, 𝐶𝑠 : o The pH of the diffusion layer surrounding a drug particle influences the solubility of ionizable drugs in the diffusion layer and hence the concentration gradient across it. ▪ The use of salt forms of drugs = ↑ dissolution rates compared to the free acid or base forms of the drugs. ▪ During dissolution of sodium salicylate in acidic media (e.g. 0.1 M HCl), ❑ the high concentration of the sodium salt close to the solid surface buffers the diffusion layer to a pH higher than the pH of the bulk medium. ❑ = ↑ solubility of the acidic drug in the diffusion layer = ↑ concentration gradient and ↑ dissolution rate. ❑ This buffering effect is not evident with solid salicylic acid in 0.1 M HCl. ❑ The 𝐶𝑠 of the free acid and the sodium salt in the bulk medium are the same. However, the sodium salt = a higher dissolution rate. 14  Noyes-Whitney Equation Diffusion layer thickness, ℎ: o influences the diffusion path length and hence the rate of dissolution. o In laboratory dissolution tests: ▪ the stirring speed and the hydrodynamics in the dissolution vessels influence the diffusion layer thickness and hence the dissolution rate. o In vivo: ▪ the peristaltic movements of the gastrointestinal tract and the composition of the gastrointestinal contents influence the thickness of the diffusion layers around the exposed surfaces of the solid drug substance. ▪ Find out: o what is the intrinsic dissolution rate? o what is the importance of the intrinsic dissolution rate? 15  Dissolution Testing USP Apparatus 1: o aka rotating basket method. o the dosage form is placed in a dry basket at the beginning of each test. ▪ Distance between inside bottom of the vessel and the basket is maintained at 25 ± 2 mm during the test o superior to USP Apparatus 2, since it constrains the dosage form in steady state fluid flow. o not suitable for testing dosage forms, which contain gums, due to the clogging. o performs well with floating dosage forms ▪ care should be taken that excipients do not clog the basket mesh. 16  Dissolution Testing USP Apparatus 2: o aka rotating paddle method. o compendial specifications outlined for this method are identical to Apparatus 1, except that the paddle is substituted for the rotating basket. o for floating dosage forms, a helix of non-reactive material is used as a ‘sinker’. o A dosage form containing high amounts of insoluble excipients is expected to form a dense mass (cone) at the bottom of the vessel. ▪ cone formation is less pronounced in cases of basket method because the dosage form does not drop to the bottom of vessel as observed the in paddle method. 17  Dissolution Testing USP Apparatus 3: o aka reciprocating cylinder method. o GIT conditions can be easily simulated, as it is easy to make time dependent pH changes. o most suitable for non-disintegrating (extended release) or delayed release (enteric coated) dosage forms. 18  Dissolution Testing USP Apparatus 4: o aka flow-through cell method o useful for: ▪ testing drugs of poor aqueous solubility in the open loop mode ▪ pH can be altered easily during a test. o disadvantages: ▪ difficult to setup ▪ difficult to clean 19  Dissolution Testing USP Apparatus 5: o aka paddle over disk o consists of a USP Apparatus 2 ▪ with the addition of a stainless steel disk assembly, designed for holding transdermal systems at the bottom of the vessel. USP Apparatus 6: o aka rotating cylinder o the vessel assembly used is the same as Apparatus 1: ▪ except the basket and the shaft is replaced with a stainless steel cylinder stirring element 20  IVIVC In-vivo/in-vitro correlation, IVIVC: o a mathematical model of the relationship between an in-vitro property of an oral dosage form (usually the rate or extent of drug dissolution or release) and a relevant in-vivo response (e.g. plasma drug concentration or amount of drug absorbed) o the Biopharmaceutical Classification System, BCS: ▪ can be used as a basis for setting in vitro dissolution specifications and in IVIVC: o for high solubility, high permeability (Class 1) drugs and, in some cases for high solubility, low permeability (Class 3) drugs: ▪ 85% dissolution in 0.1N HCl in 15 minutes can ensure that bioavailability is not limited by dissolution. 21  IVIVC In vivo/in vitro correlation, IVIVC: o for low solubility, high permeability drugs (Class 2): ▪ drug dissolution may be the rate-limiting step for drug absorption, and an IVIVC may be expected o for high solubility, low permeability drugs (Class 3): ▪ permeability is the rate controlling step, and a limited IVIVC may be possible, depending on the relative rates of dissolution and intestinal transit. o for low solubility, low permeability (Class 4) drugs: ▪ significant problems for oral drug delivery are expected. 22  IVIVC In vivo/in vitro correlation, IVIVC:. o Correlation of in-vivo results with dissolution tests is most accurate for Class 2 drugs ▪ This is because drug dissolution (and solubility) is the rate-limiting characteristic to drug absorption. o For Class 1 drugs, good IVIVCs are obtained when the drug is formulated as an extended-release product: ▪ Since solubility and permeability of the drug are accurate, absorption is controlled by its availability in the GIT. 23  Dissolution of Dosage Forms Immediate release, solid oral: o The regulatory acceptance of in vitro dissolution testing as a reliable surrogate for an in vivo bioavailability study is commonly referred to as “biowaiver.” ▪ Biowaiver may be granted for BCS Class 1 drug products for bioequivalence studies, if the drug product is rapidly dissolving. ▪ Rapidly dissolving drug product = not less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using US Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: ❑ 0.1 N HCl or Simulated Gastric Fluid USP without enzymes. ❑ a pH 4.5 buffer. ❑ a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. 24  Dissolution of Dosage Forms Powders: o Dissolution testing of finely divided particles can be performed using paddle method or flow-through cell method. ▪ There is no official method in the USP for dissolution testing of powders. Dosage forms for the oral cavity: o Sublingual tablets: ▪ USP has stated the need to use the paddle method for chewable tablets, with the exception of ampicillin chewable tablets where the basket method is suggested, and for carbamazepine chewable tablets, where both USP apparatus 2 and 3 are suggested. o Buccal tablets: ▪ In general, the drug release studies from buccal/sublingual tablets has been carried out using USP apparatus 2. 25  Dissolution of Dosage Forms Suspensions: o The USP Apparatus 2 is frequently used. Modified-release: o Extended-release: ▪ In addition to application/compendial release requirements, multipoint dissolution profiles should be obtained in three other media, for example, in water, 0.1N HCl and USP buffer media at pH 4.5 and 6.8. o Delayed release: ▪ In addition to application/compendial release requirements, dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage). ▪ This is followed by testing in USP buffer media, in the range of pH 4.5 – 7.5 (buffer stage) under standard test conditions and two additional agitation speeds (i.e. three additional test conditions). 26  Dissolution of Dosage Forms Suppositories: o typically, the suppository is placed in a dialyzing bag made of special membrane or cellophane material. ▪ The bag is placed in a beaker or wide-mouth bottle, containing a known volume of distilled water, and then concentration of the drug outside the bag is measured as a function of time. o A slight variation of the basket method is also used where the mesh is substituted by slots to provide a suitable porosity. ▪ The use of such a basket prevents blockade of the mesh. ▪ The system also has the advantage of being capable of testing suppositories that float or have such low specific gravity that it interferes with the flow dynamics of the paddle method. 27  Dissolution of Dosage Forms Topical dosage forms (creams, ointments, gels): o an open chamber diffusion cell system, such as a Franz cell system, fitted usually with a synthetic membrane is used. ▪ The dosage form is placed on the upper side of the membrane, in the open donor chamber of the diffusion cell ▪ A sampling fluid is placed in a receptor cell on the other side of the membrane. ▪ Diffusion of drug from the topical product across the membrane is monitored by an assay of samples of the receptor fluid. 28  Further Reading Sinko, P. J., & Martin, A. N. (2006). Martin's physical pharmacy and pharmaceutical sciences: Physical chemical and biopharmaceutical principles in the pharmaceutical sciences. Philadelphia: Lippincott Williams & Wilkins. Aulton, M. E. (2002). Pharmaceutics: The science of dosage form design. Edinburgh: Churchill Livingstone. Banker, G. S., & Rhodes, C. T. (2002). Modern pharmaceutics. New York: Marcel Dekker. 29 END OF LECTURE UNIVERSITY OF HEALTH AND ALLIED SCIENCES School of Pharmacy