Biopharmaceutic considerations in Drug Product Design

Biopharmaceutic considerations in Drug Product Design

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  Biopharmaceutic Considerations inDrug Product Design Riazul Islam Master of Science in Pharmaceutical Technology University of Asia pacific-UAP 1. Biopharmaceutics Drug product performance is defined as the release of the drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity. Advances in pharmaceutical technology and manufacturing have focused on developing quality drug products that are safer, more effective, and more convenient for the patient.  Biopharmaceutics examines the interrelationship of 1. The physical/chemical properties of the drug, the dosage form (drug product) in which the drug is given. 2. The route of administration on the rate and extent of systemic drug absorption. 3. The importance of the drug substance and the drug formulation on absorption. 4. In vivo distribution of the drug to the site of action. These are described as a sequence of events that precede elicitation of a drug's therapeutic effect. 2. The physical/chemical properties of the drugs Impacting Oral Absorption 2.1. Rule of 5 Molecular Weight , Log P , the Number of H-Bond donors and acceptors, Polar surface area, and the number of rotational bond. 2.2. Chirality The drug absorption process is likely to be stereospecific when mediated by carrier molecules. In addition, when chiral excipients are used in the formulation of enantiomers, interaction between them may result in stereoselective release from the dosage form. Many enantioselective drugs are usually marketed as racemates, although their therapeutic benefits are attributed only to specific enantiomers.
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  2.3. Dissolution In orderfor absorption to occur, a drug or a therapeutic agent must be present in solution form. When solid particles are in the GI tract, a saturated layer of drug solution builds up very quickly on the surfaces of the particles in the liquid immediately surrounding them. The drug molecules then diffuse through GI content to the lipoidal membrane where diffusion across the gastrointestinal membrane and absorption into the circulation takes place.  There are two possible scenarios for drug dissolution: A. Absorption from solution takes place following the rapid dissolution of solid particles. In this case, the absorption rate is controlled by the rate of diffusion of drug molecules in GI fluids and/or through the membrane barrier. B. Absorption from solution takes place following slow dissolution of solid particles. In this process, the appearance of drug in the blood (absorption) is controlled by the availability of drug from solid particles into the GI fluid. 2.4. Noyes–Whitney Equation The Noyes-Whitney equation can give a clear understanding about the drug dissolution process.  The Noyes–Whitney equation tells us that the dissolution rate (dC/dt) of a drug in the GI tract depends on 1. Diffusion coefficient (D) of a drug 2. Surface area (S) of the un-dissolved solid drug 3. Saturation, or equilibrium, solubility (Cs) of the drug in the GI fluid 4. Thickness of the diffusion layer (h) 3. The importance of the drug substance and the drug formulation The main purpose of incorporating a drug in a delivery system is to develop a dosage form that possesses the following attributes:  Contains the labeled amount of drug in a stable form until its expiration date.  Consistently delivers the drug to the general circulation at an optimum rate and to an optimum extent.  Is suitable for administration through an appropriate route.  Is acceptable to patients.
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  All the physicochemicalproperties of drugs (i.e. particle size, pH, pKa, salt form, etc.) will contribute to the dosage form design. Additionally, additives incorporated into the dosage form (e.g. diluents, binders, lubricants, suspending agents) often may alter the absorption of a therapeutic agent from a dosage form. 4. Solubility Solubility is one of the most important properties impacting bioavailability because of its role in dissolution. It is one of two factors defining the biopharmaceutics classification system (BCS). Having a good understanding of factors affecting solubility is crucial to our ability to address deficiencies in formulation caused by poor solubility. 4.1. Factors Contributing to Poor Aqueous Solubility Two main factors governing aqueous solubility are heat of solvation and heat of fusion. The octanol/water partition coefficient (log P) is a good measure of the solvation energy, which is the energy associated with dissolving solute in water. Lipophilic compounds do not like to interact with water, thus the heat of solvation is small and not enough to overcome the strong hydrogen bonds between water molecules, leading to poor solubility. If the compound is crystalline, additional energy, characterized as heat of fusion, is also required to liberate the molecule from its crystal lattice before it can dissolve. Melting point is the property that is most useful in term of characterizing crystal packing interactions. Compounds with high melting point and large heat of fusion will have poor aqueous solubility unless this large heat of fusion is surpassed by the heat of solvation. 5. pH--partition theory of drug absorption ionization is a fundamental property and occurs when drugs containing acidic or basic groups dissolve in an aqueous body fluid. [Acidic drug]  [Acidic drug]- + H+ [Basic drug] + H+  [Basic drug – H] + In general terms, the ionized form of the molecule can be regarded as the water-soluble form and the un-ionized form as the lipid-soluble form. The extent of ionization of a drug depends on the strength of the ionized group and the pH of the solution. The extent of ionization is given by the acid dissociation constant Ka. Conjugate acid  Conjugate base + H+
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  Ka = [conjugatebase] [H+]/ [conjugate acid] =Products/Reactants Strongly acidic groups (such as Drug–SO3H) have a pKa of 1–2, while weakly acidic groups (such as a phenolic–OH) have a pKa of 9–10. Strongly basic groups (such as R–NH2 where R is an alkyl group) have a pKa of 10–11, while weakly basic groups (such as R3N) have a pKa of 2–3. The dissociation constant, expressed as pKa, the lipid solubility of a drug, as well as the pH at the absorption site often dictate the magnitude of the absorption of a drug following its availability as a solution. The interrelationship among these parameters (pH, pKa and lipid solubility) is known as the pH–partition theory of drug absorption. This theory is based on the following assumptions: 1. The drug is absorbed by passive transfer 2. The drug is preferentially absorbed in unionized form 3. The drug is sufficiently lipid soluble The fraction of drug available in unionized form is a function of both the dissociation constant of the drug and the pH of the solution at the site of administration. The dissociation constant, for both acids and bases, is often expressed as -log Ka, referred to as pKa. 5.1. For weak acids Ionization of weak acids is described by an adaptation of a classical Henderson–Hasselbalch equation. As the pH of the solution increases, the degree of ionization (percentage ionized) also increases. So weak acidic drugs are highly ionized in basic medium and slowly ionized in strong acidic medium. Hence, weak acids are preferentially absorbed at low pH. 5.1. For weak bases For weak bases, the Henderson–Hasselbalch equation takes the following form:
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  As the pHof the solution increases, the degree of ionization (percentage ionized) decreases. Therefore, weak basic drugs are preferentially absorbed at higher pH. So weak basic drugs are highly ionized in strong acidic medium and slowly ionized in basic medium. Hence, weak acids are preferentially absorbed at high pH. For instance: aspirin, a weak acid with pKa of ≈3.47–3.50, has a greater fraction ionized in a more alkaline (higher pH) environment erythromycin, a weak base with pKa of 8.7, has a greater fraction ionized in a more acidic (lower pH) environment. Again, pka value higher means basic drugs, in contrast lower means acidic drugs 6. Physicochemical Properties and Drug Delivery Systems Oral bioavailability depends on several factors, mainly solubility and dissolution rate in the gastric and intestinal fluids, permeability, and metabolic stability. The effect of physicochemical properties of drugs on bioavailability is mainly on the availability of the drug at the absorption sites. Nowadays, formulation strategies have been far more successful in improving the bioavailability of compounds with poor solubility, poor dissolution rate, and poor chemical stability in acidic environments. The effect on permeability is mainly by the molecular properties, and is more effectively addressed by molecular design than by drug delivery systems. Although many studies have been reported to enhance permeability through the use of absorption enhancers such as medium chain fatty acids, bile salts, surfactants, liposacharides, and chitosans, because of the safety concerns associated with the effect of these absorption enhancers on the cell membranes, their applications in drug products are still very limited. Having a good understanding of the key physicochemical properties of the drug substance should not only help us understand the causes of low oral absorption but also guide us in defining the appropriate formulation strategies to improve bioavailability.