Dosage Form Design

1. Dosage Form Design Murat Kizaibek

2. The Need for Dosage Forms

3. The Need for Dosage Forms • To provide the mechanism for the safe and convenient delivery of accurate dosage • To protect the drug substance from the atmosphere • To protect the drug substance from the gastric acid (EC tablet) • To conceal the bitter, salty, or offensive taste or odor • To provide liquid preparations of insoluble drugs

4. The Need for Dosage Forms (continued) • To provide clear liquid dosage forms (solutions) • To provide rate-controlled drug action • To provide topical drug action (ointments, creams, patches, ophthalmic, otic, nasal) • To provide for insertion into body cavity • To provide for placement into bloodstream • To provide for inhalation therapy

5. General Considerations in Dosage Form Design

6. the nature of the illness --normally (systemic use or oral) : tablet or capsule --an emergency in which the patient may be comatose or unable to take oral medication: injection --motion sickness, nausea,and vomiting: tablets and skin patches are used for prevention and suppositories and injections for treatment.

7. age --infants and children younger than 5 years of age: flavored liquid preparations --young patient who has a productive cough or is vomiting, gagging, or simply rebellious: injection, suppository • anticipated condition of the patient --patients who have difficulty in swallowing tablets whole:chewable tablets

8. Design of Drug Products • Effectiveness • Safety • Reliability • Stability • Physical • Chemical • Microbiological

9. Design of Drug Products (continued) • Pharmaceutical elegance • Appearance • Organoleptic properties • Convenience • Ease of use • Dosing frequency • Consumer acceptance

10. Preformulation Studies • Chemical characterization • Physical characterization

11. Physical Description • Solids, liquids, gases • Chemical Properties • Structure, form, reactivity • Physical Properties • particle size, crystalline structure, melting point, solubility • Biological Properties • Ability to get to site of action and elicit a response • Herbal medicines: • powder of herbs or extracts, viscosity

12. Microscopic Examination • Particle size • Particle size range • Crystal structure • Particle shape

13. Heat of Vaporization • the amount of heat required to convert 1g of a liquid into the vapor without a change in temperature and is measured in calories. • Vapor pressure （aerosol） • Volatile drugs can migrate within a solid dosage form • Personnel exposure

14. Melting Point • Purity determination • Identity

15. The Phase Rule • Phase diagrams • Phase diagrams are valuable for interpreting interactions between two or more components, relating not only to melting point depression and possible liquefaction at room temperature but also the formation of solid solutions, coprecipitates, and other solid-state interactions.

16. The following characteristics of a drug substance are affected by the particle size distribution: Particle Size • Dissolution rate • Bioavailability • Content uniformity • Taste • Texture • Color • Stability • Flow characteristics • Sedimentation rates

17. Polymorphism • Crystalline form • Amorphous form • at least one third of all organic compounds exhibit polymorphism. • Melting point variation • Solubility differences

18. Solubility • Some aqueous solubility required for therapeutic efficacy • Equilibrium solubility • Solubility in different solvents • Chemical modification of the drug into salt or ester forms is frequently used to increase solubility.

19. Solubility and Particle Size • Small increases in solubility can be achieved by particle size reduction. • Decreases in particle size may enhance dissolution rates.

20. Solubility and pH • pH can affect solubility.

21. Dissolution • Dissolution may be rate-limiting step in the absorption of poorly soluble drugs. • Can affect onset, intensity, and duration of response and control overall bioavailability of the drug from the dosage form

22. Membrane Permeability • pKa, solubility, and dissolution rate data can provide an indication of absorption.

23. pKa/Dissociation Constants • Extent of dissociation or ionization • Dependent on pH of medium • Can affect absorption, distribution, and elimination

24. Partition Coefficient • Octanol:water partition coefficient often used in formulation development

25. Drug and Drug Product Stability • Physical stability • Chemical stability • Shelf life of 2-3 years is generally desired

26. Drug Stability: Mechanisms of Degradation • Hydrolysis, solvolysis • Oxidation • Other processes

27. Drug and Drug Product Stability: Kinetics and Shelf Life • Chemical stability:active ingredient retains its chemical integrity and labeled potency within the specified limits. • Physical stability:appearance, palatability, uniformity, dissolution, and suspendability • Microbiological stability:microbial growth • Therapeutic stability:The therapeutic effect remains unchanged. • Toxicologic stability:No signifi cant increase in toxicity occurs.

28. Rate Reactions • Change of drug concentration with respect to time

29. C C t lnC t t ZERO-ORDER RATE REACTIONS FIRST-ORDER RATE REACTIONS

30. Q10 Method of Shelf Life Estimation • Shelf life estimation Reasonable estimates can often be made using the Q value of 3.

31. Enhancing Stability of Drug Products • Excipients may be added to protect the drug • Antioxidants • Preservatives • Chelating agents • Buffering agents

32. Stability Testing • Done at each stage of product development • Product containers and closures must be considered • Temperature and humidity studies • Light studies • Changes in physical appearance, color, odor, taste, texture • Chemical changes of drug degradation • Pharmacist is last professional to check for quality and stability prior to dispensing

33. Herbal drugs: preformulation

34. 1. processing • 2. powder of extract or powder of plant material? • 3. volatile? • 4. taste or odor • 5. solvent of extraction? • 6. dense and hard materials • 7.bioguided fractionation