Goals of Preformulation

1. Goals of Preformulation • Establish the necessary physicochemical parameters of a new drug substance. • Determine drug kinetic rate profile. • Develop a stability indicating assay. • Establish drug compatibility with common excepients.

2. Goals of Preformulation • Establish the necessary physicochemical parameters of a new drug substance. • Determine drug kinetic rate profile. • Develop a stability indicating assay. • Establish drug compatibility with common excepients.

3. Compatibility tests Types of incompatibility ?

4. Compatibility tests Aim ? Which excepient Which Drug/Excepient ratio

5. Compatibility tests Methods ? Solid dosage form Liquid dosage form FDA Guidelines

6. Compatibility test for solid dosage forms Stopper + Wax Drug + Excepient Room Temperature 55oC Without water With water Without water With water Compare to drug stored under same conditions

7. Compatibility test for solid dosage forms Stopper + Wax Drug + Excepient Room Temperature 55oC Visual examination Quantitative relation of certain excepient character and interaction rate Analytical assay

8. Compatibility test for liquid dosage forms Aqueous solution Non-aqueous solution Parenteral Oral

9. Compatibility test for liquid dosage forms Aqueuos solution compatibility Parentral Oral Drug + Excepient solution • -Heavy metals • Heavy metals+chelating agent • Oxygen and nitrogen atmosphere • Autoclaving • Different blugs • -Ethanol • Glycerin • Sucrose • Preservative • Buffers

10. Compatibility test for liquid dosage forms Aqueuos solution compatibility Parentral Oral Drug + Excepient solution Visual examination Analytical assay

11. Compatibility tests Drug : Excipient ratio The preformulation screening of drug-excipient interaction requires (1 : 1) Drug:excipient ratio, to maximize the likehood of observing an interaction. ??? Some researchers recommend ratios of : 1:5 for diluents 3:1 for binder & disintegrants 5:1 for lubricant 10:1 for colourant

12. Compatibility tests Analytical Methods Chromatography Vapour Pressure Osmometry Accelerated Storage Testing Thermal Analysis Non-thermal Analysis Radio Labelled Techniques Fluoroscence Measurement Spectroscopy

13. Compatibility tests Methods Chromatography TLC HPLC

14. Compatibility tests Methods Chromatography TLC HPLC

15. Compatibility tests Methods Chromatography TLC HPLC Advantages : Evidence of degradation Spots or peaks isolation. Quantification to obtain Kinetic data. Changes in the chromatograph such as appearance of NEW SPOT or Peak or change in Rf values or Rt means significant interaction.

16. Compatibility tests Methods Thermal Analysis Isothermal microcalorimetry Differential scanning calorimetry Thermogravimetric analysis Calorimetry is the science of heat. It is about how a given material responds to temperature changes on both the atomic and macroscopic level. It reveals important information about the arrangement and interaction of the atoms.

17. Differential scanning calorimetry (DSC) Is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. For solid state

18. Differential scanning calorimetry (DSC) Applications It detects physical transformation such as melting, dehydration or crystallization Cross - Linking Crystallisation (Cure) > exothermic - Glass Transition Heat Flow Melting Temperature

19. Differential scanning calorimetry (DSC) Applications It detects physical transformation such as melting, dehydration or crystallization Phase equilibrium diagrams of enantiomers Compatibility of drug with excepients

20. Differential scanning calorimetry (DSC) DSC thermogram for API, Croscarmilose and physical mixture of both

21. Differential scanning calorimetry (DSC) DSC thermogram for API, Lactose and physical mixture of both

22. Heat conduction microcalorimetry • Isothermal heat conduction microcalorimetry is an analytical method allowing determination of minute amounts of evolved or absorbed heat. • The sensitivity is 10 000-fold higher than the sensitivity of conventional differential scanning calorimetry (DSC). • By microcalorimetry heat flow signals in the range of µW are detectable. • The rate of heat flow is proportional to the rate of the process taking place.

23. Heat conduction microcalorimetry Fig. 8. Concentration dependent drug-associated heat flow at 258C for a drug concentration of 8.7% NEA and various concentrations of E2-hemihydrate

24. Heat conduction microcalorimetry For a reaction A + B = C + D First order Zero order

25. Heat conduction microcalorimetry 80oC 20 75oC Ø 10 Zero-order 0 -10 1 2 Time (days)

26. Heat conduction microcalorimetry Applications Heat conduction microcalorimetry detects chemical changes. BUT it gives no direct information about the chemical nature of the reaction For liquid and solid state

27. Heat conduction microcalorimetry Applications Drug stability Drug/excepient compatibility Liquid state Solid state -Oxidation -Decomposition -Kinetics -Kinetics -crystallization

28. Thermogravimetric analysis • Measures the amount and rate of change in the weight of a material as a function of temperature or time in a controlled atmosphere. • Measurements are used primarily to determine the composition of materials and to predict their thermal stability at temperatures up to 1000°C. • The technique can characterize materials that exhibit weight loss or gain due to decomposition, oxidation or dehydration.   For solid state

29. Compatibility tests Methods Non-thermal Analysis X-ray diffraction FT-IR Spectroscopy

30. FT-IR Spectroscopy • Is the absorption measurement of different IR frequencies by a sample positioned in the path of an IR beam. • Different functional groups absorb characteristic frequencies of IR radiation. • The main goal of IR spectroscopic analysis is to determine the chemical functional groups in the sample.

31. FT-IR Spectroscopy

32. FT-IR Spectroscopy Common Applications • Identification of compounds by matching spectrum of unknown compound with reference spectrum (fingerprinting) • Identification of functional groups in unknown substances. • Identification of reaction components and kinetic studies of reactions • Detection of molecular impurities or additives present in small amounts . • Analysis of formulations such as insecticides and copolymers

33. FT-IR Spectroscopy Detects chemical interations For liquid and solid state K. A.Mohammed, H. K. Ibrahim, M. M. Ghorab, Drug Deliv, 2014.

34. X-ray diffraction • X-rays interact with crystalline substances to give a diffraction pattern. • The X-ray diffraction pattern of a pure substance is like a fingerprint of the substance. • In a mixture of substances, each produces its pattern independently of the others. • The powder diffraction method is thus ideally suited for characterization and identification of polycrystalline phases.

35. X-ray diffraction

36. Transdermal nonaqueuos solution compatibility -Compatibility with different excepients -Release and permeation characteristics In vitro In vivo With membrane (ex-vivo) Without membrane

37. Nonaqueuos solution compatibility 110 Flux of oily solution release Flux of solution+membrane release 100 Amount released 90 90 6 12 18 24 Time (units) Chein et al., Drug Dev Ind Pharm, 1983.

38. Transdermal nonaqueuos solution compatibility -Compatibility with different excepients -Release and permeation characteristics In vitro In vivo With membrane (ex-vivo) Without membrane Sacrifice

39. Emulsion compatibility Preformulation is very formulation oriented: -Surfactant selection -Calculation of surfactant amount -Measuring CMC -Calculating the required HLB -pH stability profile of the surfactant in presence of other emulsion components

40. Emulsion compatibility Micro/nanoemulsion

41. Gel compatibility Preformulation is very formulation oriented: -Polymer selection -Drug stability in the gel

42. Preformulation studies → expected outcomes • The product will: • Meet specifications (assay, impurities & dissolution rate) • Be consistent within & between batches. • Is palatable to the patient. • Have optimum chemical & physical stability. • Fewer formulations fail stability & BA studies • Have cost effective manufacture.