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. Types of incompatibility
Compatibility tests
Types of incompatibility ?

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

5. ? Compatibility tests FDA Guidelines 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
Analytical assay
Quantitative relation of certain excepient character and interaction rate

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

19. Applications Differential scanning calorimetry (DSC)
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 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
Time (days) 1 2
-10 10 20 Ø
80oC
75oC
Zero-order

26. For liquid and solid state
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. Drug/excepient compatibility
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. Detects chemical interations For liquid and solid state
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
Time (units) 6 12 18 24 90
100
110
Amount released
Flux of oily solution release
Flux of solution+membrane release
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.