Purpose of the BCC Guidance: Expands the regulatory application of the BCC and recommends methods for lassoing drugs. Explains when a waiver for in vivo availability and bougainvillea studies may be requested based on the approach of BCC. Goals of the BCC Guidance: To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bougainvillea tests. To recommend a class of immediate-release (IR) solid oral dosage forms for which bougainvillea may be assessed based on in vitro dissolution tests.
To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance. Classification: According to BCC, drug substances are classified as (Figure 3): Class I : High Solubility – High Permeability Class II : Low Solubility -? High Permeability Class Ill: High Solubility – Low Permeability Class IV: Low Solubility – Low Permeability CLASS BOUNDARIES A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7. 5.
A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. A drug reduce is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USPS apparatus or II in a volume of < 900 ml buffer solutions. Class I drugs exhibit a high absorption number and a high dissolution number. The rate limiting step is drug dissolution and if dissolution is very rapid then gastric emptying rate becomes the rate determining step. e. g.
Meteorology, Idealized, Vertebral, proportional. Class II drugs have a high absorption number but a low dissolution number. In vivo drug dissolution IS then a rate limiting step for absorption except at a very high dose number. The absorption for class II drugs is usually slower than class II and occurs over a longer period of time. In vitro- In vivo correlation (VICE) is usually accepted for class I and class II drugs. E. G. Phenotype, Donald, Coeducational, Mainframe acid, Infinitive. For Class Ill drugs, permeability is rate limiting step for drug absorption. These drugs exhibit a high variation in the rate and extent of drug absorption.
Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. E. G. Commenting, Acyclovir, Neomycin B, Capacitor. Class IV drugs exhibit a lot of problems for effective oral administration. Fortunately, extreme examples of class IV compounds are the exception rather than the rule and are rarely developed and reach the market. Nevertheless a number of class IV drugs do exist. E. G. Tax. Combined with the dissolution, the BCC takes into account the three major factors governing availability biz. Solution, solubility and permeability. Determination of solubility: The solubility of a substance is the amount of substance that has passed into solution when equilibrium is attained between the solution and excess, I. . Undisclosed substance, at a given temperature and pressure. A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous medium over the pH range of 1-7. 5 (1 The volume estimate of 250 ml is derived form the typical volume of water consumed during the oral administration of dosage form, which is about a glassful, or 8 ounces of water.
This boundary value is a reflection of the minimum fluid volume anticipated in stomach the time of drug administration. The pH solubility profile of the drug substance is determined t 37 В± OIC in aqueous medium with pH in the range of 1-7. 5. A sufficient number of pH conditions should be evaluated to accurately define the pH- solubility profile. The number of pH conditions for a solubility determination depends upon unionization characteristics of the test drug substance.
A minimum of three replicate determinations of solubility in each pH condition should be carried out. Standard buffer solutions described in pharmacopoeias are considered appropriate for use in solubility studies. If these are not suitable for physical or chemical reasons, other buffer solutions an also be used provided the pH of these solutions are verified. Methods other than shake flask method are also used with justification to support the ability of such methods to predict equilibrium solubility of test drug substance. E. G. Acid or base titration methods. The concentration of drug substance in selected buffers or pH conditions should be determined using a validated solubility-indicating assay that can distinguish between the drug substance from its degradation products. If degradation of drug is observed as a function Of buffer composition and/or pH, it should be taken into consideration. Determination of permeability: Fundamental to understanding of the nature of gastrointestinal permeability limitations are methods and technique sues to both screen and grade these characteristics.
These methods range from simple oil/water (O/W) partition coefficient to absolute availability studies. The methods that are routinely used for determination of permeability include: a. Human studies Mass balance studies Absolute availability studies Intestinal perfusion methods b. In vivo or in situ intestinal perfusion in a suitable animal model c. In vitro permeability methods using excised intestinal tissues d. Monolayer’s Of suitable epithelial cells e. G. Cacao-2 cells or ETC-7 cells In mass balance studies, unlabelled, stable isotopes or radionuclide drug substances are used to determine the extent of drug absorption.
However this method gives highly variable estimates and hence other methods are sought for. In absolute availability studies, oral availability is determined and compared against the intra venous availability as reference. Intestinal perfusion models and in vitro methods are recommended for passively transported drugs. The observed low permeability of some drug absences in human could be attributed to the efflux of drug by various membrane transporters like p-globetrotting. This leads to misinterpretation of the permeability of drug substance.
An interesting alternative to intestinal tissue models is the use of well-established in vitro systems based on the human demarcation cell line Cacao-2. These cells serve as a model of small intestinal tissue. The differentiated cells exhibit the microvolt typical of the small intestinal mucosa and the integral membrane proteins of the brush- border enzymes. In addition, they also form the fluid-filled domes typical of a remarkable epithelium. Recent investigations of Cacao-2 cell lines have indicated their ability to transport ions, sugars and peptides.
The directed transport of bile acids and vitamin EBB across Cacao-2 cell lines has also been observed. These properties have established the Cacao-2 cell line as a reliable in vitro model of the small intestine. Determining Drug Product Dissolution Characteristics Dissolution testing should be carried out in USPS Apparatus I at 100 RPM or Apparatus II at 50 RPM using 900 ml of the following dissolution media: (1) 0. 1 N HCI or Simulated Gastric Fluid USPS without enzymes; (2) a pH 4. 5 buffer; ND (3) a pH 6. 8 buffer or Simulated Intestinal Fluid USPS without enzymes.
For capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USPS (with enzymes) can be used. The JSP Apparatus I (basket method) is generally preferred for capsules and products that tend to float, and USPS Apparatus II (paddle method) is generally preferred for tablets. For some tablet dosage forms, in vitro (but not in vivo) dissolution may be slow due to the manner in which the disintegrated product settles at the bottom of a dissolution vessel. In such situations, USPS Apparatus may be preferred over Apparatus II.