Name : Mutiara FaridaClass : V A

ID : 1201002STIFARM PADANG

Dissolution (the drug release from the dosage form) is a very important thing for all preparations, whether made in conventional, solid oral dosage forms in general, as well as dosage forms with modified release, and may be the rate-limiting step for the absorption of drugs given orally.

Concept dissolution Dissolution refers to the process when

the solid phase (eg tablets or powder) into the solution phase, such as water.

In essence, when the drug dissolves, separating solid particles and molecule by molecule mixed with liquid and seems to be part of the liquid Dissolution of drugs a process when the drug molecules were released from the solid phase and enter into the solution phase.

release Dissolution, The physicochemical is the process by which solid phase into the solvent to produce a solution.

Dissolution of drug compounds is a multistep process that involves a multi-heterogeneous reaction / interaction between solute-solute phase (solute-solute) and solvent-solvent phase and the solute-solvent interface.

Which is a heterogeneous reaction process overall mass transfer can categorized as a) the removal of the solute from the solid phase, b) accommodation of the solute in the liquid phase, and c) diffusive and / or convective transport of solutes from the solid / liquid interface to the bulk phase.

Based on the perspective of the dosage form, dissolution of the active substance is not a disintegration of the dosage form. (Kramer et al. 2005).

Correlation of in vitro - in vivo is a predictive mathematical model that describes the relationship between the in vitro properties of an oral dosage form (usually large rate or dissolution / drug release) and related responses in vivo (eg, plasma drug concentration or amount of drug absorbed ) Patterns of drug release and dissolution generally divided into 2 groups: the zero-order release and first order.

Obtained from the zero-order release of the dosage form is not berdisintegrasi, such as topical delivery systems / transdermal depot implantation systems, or systems with controlled drug delivery.

Dissolution rate data will only be meaningful if the test results in a sequence of the same stocks, consistent within acceptable limits.

Dissolution test should give reproducible results, even if carried out in different laboratories by different personnel.

Therefore, to achieve high reproducibility, all the variables that can affect the test should be well understood by the controlling possibilities.

The factors that affect the rate of dissolution a drug from the preparations can include: _ The factors related to the physico chemical properties of the drug _ The factors related to the drug formulation _ The factors associated with dosage forms _ The factors related to the dissolution test equipment _ The factors related to the test parameters disolus _ Various other factors

Dissolution rate factors affecting drug related physicochemical properties_ Factors affecting solubility _ Polymorphism _ The state of amorphous and solvate _ Free acid, free base, or a salt form _ The formation of complexes, solid solutions, and mixtures eutektikum _ The particle size _ surfactants

Factors affecting surface area (available) for dissolution: _ The particle size _ Variable-making Some physicochemical properties of active substances that affect the dissolution characteristics are: _ Ionization constants (pK), _ Solubility as a function of pH, the stability of the solution as a function of pH, Particle size, Crystal form, Ionic strength, Ionized form, and Buffer effect .

Factor affecting the associated dissolution rate formulation development method :_ The number and types of excipients, such as

neutral salt _ Type of manufacture of tablets used _ Granule size and granule size distribution amount and type of crushers and methods _ mixing _ The amount and type of surfactant (if added) as well as the mixing method _ Style compression and compression speed.

Tool Indonesian Pharmacopoeia dissolution test according to the fourth edition: _ Tool basket type dissolution test (basket) _ Tool paddle type dissolution test (paddle) _ Tool drug release test (USP 29, NF 24): _ Drug release testing devices such as baskets (basketball) _ Drug release testing devices such as paddle (paddle)

Test equipment such as reciprocating cylinder drug release _ Drug release testing devices such as flow-through cell _ Drug release testing devices such as paddle over disk _ Test equipment in the form of drug release cylinder (cylinder) _ Test equipment such as reciprocating holder drug release

The dissolution test determines the cumulative amount of drug that goes into solution as a function of time. As shown in Figure 1, dissolution of drug from a dosage form involves at least two consecutive steps: liberation of the solute or drug from the formulation matrix (disintegration), followed by dissolution of the drug (solubilization of the drug particles) in the liquid medium. The overall rate of dissolution depends on the slower of these two steps.

The relative difference in rates should be carefully considered when designing the dissolution method. The cohesive properties of the formulated drug play a key role in the first step of dissolution. For solid dosage forms, these properties include disintegration and erosion; whereas for semisolid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor. If the first step of dissolution is rate limiting, then the rate of dissolution is considered to be disintegration controlled. Careful assessment of the intrinsic rate of dissolution and the effect of various aspects of the formulation (e.g.,release profiles from precompressed granules, impact of compression force, porosity, and lubrication) can reveal the relative contribution of the disintegration step to the overall dissolution of the drug form.

In the second step of dissolution—solubilization of the drug particles—the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical (e.g., amorphous or polymorph, and primary particle size) play an important role. If this latter step is rate limiting, then the rate of dissolution is intrinsic dissolution controlled. This is the case for most poorly soluble compounds in IR formulations. For poorly soluble compounds in solubilized formulations, in vivo precipitation also may need to be considered when developing a dissolution test method, in particular for establishing an IVIVR or IVIVC.

Dissolution is a process in which a solid substance solublizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Several theories to explain drug dissolution have been proposed some of the important one’s are…

• Diffusion layer model /film theory.• Danckwert’s model/penetration (or)

surface renewal theory.• Interfacial barrier model/double barrier (or)

limited solvation theory.

According to Noyes-Whitney’s Equation: dc/dt =k s(cs-c)-----------------------(1)Where :

dc/dt= Dissolution rate of the drug K= Dissolution rate Constant Cs = Concentration of drug in the stagnant

layer C = Concentration of drug in the bulk of the

solution at time t S =Surface area of the particles

When a solid is introduced into the dissolution medium, the volume of fluid immediately adjacent to its solid surface gets saturated with the drug. The thin stationary film of solution around the solid surface is called diffusion layer the concentration in this layer is equal to cs. The thickness of the diffusion layer is ‘h’ .The dissolution rate constant rate can be expressed as

K= D/h -----------------------(2)Where : D = Diffusion coefficient of the drug in solution H = Thickness of the diffusion layer

Danckwert’s apposed the existence of stagnant layer by assuming that turbulence in the dissolution medium exists at the solid/liquid interface.

He suggested that the agitated fluid contains macroscopic mass of eddies (or) packets reach the solid/liquid interface in a random fashion due to eddy currents, absorb the solute by diffusion and carry it to the bulk of the solution. Such solute containing packets are continuously replaced with new packets of fresh solvent due to which the drug concentration at the solid/liquid interface never reaches cs and has a lower limiting of ci.since the solvent packets are exposed to new solid surface each time, this theory is also called surfacerenewal theory

Danckwert’s model is expressed by equn :V dc/dt = dm/dt = A (Cs-Cb). (γD) ½Where :

• V=volume of dissolution medium.• dc/dt=dissolution rate of the drug.• m=mass of solid dissolved.• A=surface area of the dissolving solid.• Cs = Concentration of drug in the stagnant

layer.• Cb = Concentration of drug in the bulk of the

solution at time t.• D=diffusion coefficient (diffusivity) of the drug.• γ = rate of surface renewal(or)the interfacial

tension.

The diffusions layer model and Danckwerts model are based on two assumptions.1.Rate determining step that contains dissolution in the mass transport.2.solid-soln equilibrium is achieved at the soild liquid interface.

• According to the interfacial barrier model:An intermediate concentration can exist at the interface as result of solvation mechanism and function of solubility rather than diffusion. When considering the dissolution of a crystal, each face of the crystal will have a different interfacial barrier such a conceptis given by the following equn.

G=Ki(cs-cb)

Where : G=dissolutionte rate per unit area Ki =effective interfacial transport constant. Cs = Concentration of drug in the stagnant

layer Cb =Concentration of drug in the bulk of the

solution at time tIn this theory, the diffusity D may not be

independent of saturation concentration cs. Therefore the interfacial model can be extended to both diffusion layer model and Danckwerts model.

A Text Book Biopharmaceutics and pharmacokinectics by Gibaldi

A Text Book of Principles and applications of Biopharmaceutics and pharmacokinectics by Dr.H.P.Tipins & Dr.Amirta Raj.

A Text Book of Physical Pharmaceutics by C.V.S Subrahmanyam

Indonesian of pharmacope USP 29, NF 24

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