DISSOLUTION AND COMPARATIVE DISSOLUTION PROFILE (PDC)
Both for Dissolution and for Dissolution Profile, in a simplified way, it is sought to understand the process in which the active or drug is released from the pharmaceutical form to become available for the absorption process in the body.
As an in vitro laboratory test is to determine how much the active substance or drug becomes soluble in a given liquid (medium). In this way the solubility of capsules, tablets, suspensions, transdermal patches, vaginal rings can be evaluated, ensuring the quality of the formulations during development.
Dissolution involves time to the solubilization or release of the drug. In this way the dissolution tests for drugs can be classified as:
I. Single-point dissolution test;
II. Two-point dissolution test;
III. Dissolution profiles obtained from the dissolved drug percentage at different sampling times.
The dissolution profile (PD), when compared to other similar products in pharmaceutical form and presentation, is called the comparative dissolution profile (PDC). It is the dissolution kinetics of the active pharmaceutical form, solid, suspension, semisolid, transdermal patches, vaginal rings, among those required. The kinetics have in their axes the% of the drug released (dissolution) x release time, as shown in the graphs below.
The PDC is a formal request from ANVISA for registration of new, similar and generic drugs. The result of the PDC allows to observe the similarity of dissolution at different times, in this way it is possible to verify the proportionality between dosages, moments of dissolution for a prediction to bioequivalence.
When you need the PDC:
It is a comparative "iv" (in-vitro) result between two formulations. In this way it will be necessary to present it when changing manufacturing site, change of manufacturer of inputs, as an indispensable prerequisite for the study of Bioavailability / Bioequivalence and meeting the requirements of ANVISA.
For the dissolution test or dissolution profile it is necessary to have the definition of the medium (liquid in which exposure of the drug containing product will occur to observe its release). If no such medium is available, either by compendial studies or by methods indicative of stability, it is necessary to obtain the DISSOLUTION DOSSIER. The dissolution dossier is a complex study in which different apparatus, different media, different pHs, Q value challenge, or challenges requested in DRC 31 of August 11, 2010 are used.
The main means of dissolution are described below, but research and apparatus, may define new, but must be submitted to official bodies for approval. In order for the asset to dissolve, the solubility factor must be considered. In this case the means considered for the dissolution of the asset are those that approach the "in-vivo" relationship.
Means considered most common:
· Water; HCl 0,1molar pH = 1,2
· Phosphate Buffer pH = 5,8 a 7,2
· Acetate buffer pH = 4,1 a 5,5
Enzyme media - aqueous medium:
· Simulated Gastric Juice (pepsin / NaCl / HCl pH 1.2);
· Simulated Gastric Sickness / Enzyme (NaCl / HCl pH 1.2);
· Simulated Enteric Booster (pancreatin / NaH2PO4 / NaOH pH 6.8);
· Sodium hydroxide at pH> 7.0 to 10.0 (examples: diosmin / spiridin-pH = 9.0, isotretinoin-pH = 10);
· Polysorbate 20 in 0.1 N HCl + pepsin;
· Means with high surfactant content;
SEMI-SOLID PRODUCTS: According to DRC 31 of August 11, 2010, the dissolution profile of semisolid products are replaced by the Skin Permeation Assay, inserted in SINEB and can only be performed by laboratory authorized by ANVISA in Pharmaceutical Equivalence.
The semisolid products, such as ointment and cream, the comparative dissolution profile uses specific equipment called Transdermal Diffuser, which performs the test called Cutaneous Permeation or in vitro Performance Test.
The assay occurs in FRANZ cell which receives the semisolid separated from the medium by means of a membrane previously defined in cutoff diameter. The time of contact is stipulated, as are the collections for the analysis of the drug released through the medium through the membrane. This test evaluates the passage of a substance when added on the dermis that in systemic action occurs percutaneous absorption.
The acronym that establishes the name SINEB means: National System of Information of Studies of Pharmaceutical Equivalence and Bioequivalence. Studies such as: Skin Permeation, PDC, Pharmaceutical Equivalence, Bioenvironment, Bioequivalence are mandatory in this system "on line" of ANVISA.
To initiate a study of Bioequivalence it is necessary to have completed the study of Pharmaceutical Equivalence and be inserted in SINEB.
For the quantifications the analytical techniques will be in function of the molecule and the analytical resources employed, among the techniques most used are:
· Gas-phase Chromatography (GC-FID-ECD-TCD-MS-Head Space);
· Liquid phase chromatography (UPLC or HPLC-UV / Vis; Fluorescence; ELSD);
· LC-MS / MS: Mass Spectrometry coupled to HPLC or UPLC;
· ICP-OES (Induced-Simultaneous and Sequential Plasma);
· AA - (Atomic Absorption) and FC (photometry
of flame), Hydride Generator;
· Determination of peak purity using DAD;
· Ultraviolet and Visible Absorption;
The dissolution systems offered by the T & E Analytical Center have the following devices:
· USP Apparatus 1 - Rotary Basket;
· USP Apparatus 2 - Blades;
· USP Apparatus 5 - Shovel on disc;
· USP Apparatus 6 - Rotary Cylinder;
Note: apparatuses 5 and 6 are used for transdermal, adhesive, etc.
Conventional vats are glass or polymeric, transparent or amber. The volume and shape of the vats are important for obtaining the results.
The standard tank of a dissolutor has a volume of 900mL, are cylindrical open containers with a hemispherical bottom.
· Cube of 900mL - hemispheric fund;
· Cube of 900mL (Peek Vessel) - internal pre-drilling bottom;
· Cube of 500mL - hemispheric fund;
· Set of mini vats and mini spades - 250 ml;
Note: When changing a tank, such as the use of Peek Vessel, ANVISA should be consulted to conduct the tests, since it has a higher intensity vortex.
Note: Other techniques can be used, always depending on the structure of the molecule. Such methodologies shall be accompanied by scientific explanation and validated in accordance with the resolution in force.