Preformulation. By: Ass. Prof. Gamal Shazly

Transcription

1 Preformulation By: Ass. Prof. Gamal Shazly

2 Preformulation Testing It is the investigation of the physical and the chemical properties of the drug substance alone and when combined with formulating excipients to get information useful to the formulator in developing stable and bioavailable dosage form.

3 The preformulation testing include the following: 1-Organoleptic properties of the drug substance 2-Purity of the drug 3-Particle size, shape and surface area 4-Solubility 5-Dissolution 6-Parameters affecting absorption 7-Crystal properties and polymorphism 8-Stability 9-Miscellaneous properties

4 1-Organoleptic properties The physical description of the drug substance e.g. the colour, the odour and the taste of the new drug must be recorded using descriptive terminology If the colour is undesirable or variable, incorporation of a dye in the final product is recommended. If the taste is unpalatable,it is recommended to use the less soluble or ester form of the drug The odour and the taste may be suppressed by using suitable flavors and excipients or by coating the final product.

5 2-Purity It is necessary to detect the purity or homogenity of the drug substance,as impurities may have undesirable effects Techniques adopted for detecting purity of medicinal substances 1-Thin layer chromatography 2-High performance liquid chromatography 3-Differential and gravemetric thermal analysis 4-Hot stage microscopy by observing the sharpness in the melting point 5-Quantitative differential scanning calorimetery 6-Phase rule solubility analysis.

6 3-Particle size, shape and surface area Particle size distribution and particle shape affect various chemical and physical properties of the drug substance as well as the biopharmaceutical behavior -Poorly- water soluble drugs showing a dissolution rate limiting behavior are more bioavailable when administered in a finely subdivided state Size affects Homogeneity Efficiency of mixing of powders and granules Stability: fine materials are more open to attack from atmospheric oxygen, humidity and interacting excipients So,it is important to determine and control a desirable size range

7 Techniques used for particle size determination 1-Microscopy Estimates the range of sizes and shapes from about 0.3 microns upwards 2-Sieving or screening Used for materials range upwards from 40 microns 3-Dynamic light scattering 4-Laser Diffraction analyzer 5-Coulter counter

8 4-Solubility Aqueous solubility of drugs is an important biopharmaceutical parameter As it affects The rate of dissolution and thus affects the rate of absorption The solubility must be determined as a function of ph over the physiological ph range, ph 1-8 Methods of enhancement of solubility 1-Grinding,which decrease the particle size and increase the surface area 2-Using different types of surfactants specially non-ionic surfactants 3-Complexation with certain water-soluble complexing agents as cyclodextrins, xanthines,etc 4-Co-melting with certain hydrophilic carriers 5-Co-grinding with hydrophilic carriers 6-Co-precipitate formation with hydrophilic carriers, as PEGs, PVPs

9 5-Dissolution Rate constant of dissolution Rate constant of absorption Solid drug In the G.I.fluid Kd dissolution Drug in solution in the G.I.fluid Ka absorption Drug in systemic circulation When Kd << Ka,dissolution is significantly slower and the absorption is described as dissolution-rate limited. Intrinsic dissolution The dissolution rate of a solid in its own solution is described by Noyes-Nernst equation dc/dt=dissolution rate D=diffusion coefficient h=diffusion layer thickness A=surface area of the dissolving solid. C=solute concentration in bulk solution Cs=solute concentration in the diffusion layer V=volume of the dissolution medium When C=Cs dissolution will be stopped,so sink conditions must be maintained during dissolution.

10 6-Parameters affecting absorption The rate of permeation of the drug molecule through biological membranes depends on 1-The molecular size 2-The relative aqueous and lipid solubility 3-The ionic charge of the permeating molecules To Characterize the permeation behavior of the drug molecule there are three parameters 1-The partition coefficient 2-Ionization behavior 3-In vitro transport measurements using biological membranes

11 7-Crystal properties and polymorphism Many drug substances exist in more than one crystalline form (polymorphs Occasionally, a solid crystallizes entrapping solvent molecules in a specific position in the crystal lattice forming a solvate or pseudopolymorph Different polymorphs of a given drug differ from each other in many physical properties such as: a-solubility b-dissolution c-bioavailability d-true density e-compaction behavior f-flow properties g-tabletting behavior h-physical Stability

12 Techniques adopted for studying crystal properties and polymorphism 1-Single crystal X-Ray 2-X-Ray powder diffraction 3-IR spectrophotometery Different polymorphs show different diffraction patterns while the amorphous form does not show any diffraction pattern or shows one or two broad peaks ( halo pattern).

13 8-Stability and compatability studies It is necessary to know the stability of the drug substance to specify the expiration dating and to have an idea of what excipients to formulate with the drug to attain maximum stability For compatibility,it is necessary to detect the drug compatability with the formulated excipients,any incompatible excipient must be ommitted from the formula. The stability of the drugs is carried out by two methods 1-Accelerated stability studies in which one use stress conditions to get early and rapid information 2-Long term stability studies for determining the shelf life of the drug in the dosage form in the normal storage conditions

14 The stability of a drug to be developed in a tablet dosage form must be studied under the following categories 1-Solid state stability of the drug alone 2-Compatability studies using DSC and IR techniques (stability of the drug in the presence of excipients to detect the effect and compatibility of excipients in the formulation ) 3-Solution-phase stability(stability of the drug in the G.I. fluids and granulating solvents) 9-Miscellaneous properties A-Density Knowledge of the absolute and bulk densities of the drug substance is very useful in forming some ideas to the final dosage form

15 B-Hygroscopicity The amount of moisture adsorbed by a fixed weight of anhydrous sample in equilibrium with the moisture in the air at a given temperature is referred to as the equilibrium moisture content Absorption of moisture affect the stability of solids For formulating hygroscopic compounds 1-They should be stored in a well closed containers preferably with a desicant 2-Non-aqueous granulating solvents are used for granulation 3-Sometimes,it may be necessary to carry out the entire tabletting operation under an atmosphere of controlled humidity

16 C-Flowability The flow properties are critical for an efficient tabletting operation A good flow of powders to be compressed gives efficient mixing and acceptable weight uniformity of the compressed tablets Poorly flowable powders may have to be precompressed or pregranulated The angle of repose is the most common way of expressing flow characteristics of powders For most pharmaceutical powders, its value range from degrees,values near to 25 degrees indicating better flow characteristics

17 D-Compressibility The ability of the powders to form a compact under pressure is dependent on the compressibility characteristics Powders which form hard compacts under applied pressure without exhibiting any tendency to cap or chip is considered as readily compressible, they can be directly compressed without granulation

18 Practical Part 1) Organoleptic properties Oder Taste Colour Solubility Determine the solubility of NaCl, CaCO 3 and NaHCO 3 Term Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically insoluble Parts of Solvent Required for 1 Part of Solute Less than 1 part 1 to 10 parts 10 to 30 parts 30 to 100 parts 100 to 1000 parts 1000 to 10,000 parts More than 10,000 parts

19 2)Measurement of angle of repose: Definition: It is the maximum angle between the surface of the heap of the powder and the horizontal plane. tan θ= 2H/D = H/ ½D Where: θ : angle of repose H : height of heap D : diameter of heap

20 Factors affecting angle of repose: 1) Particle size. 2) Particle shape. 3) Particle density. 4) Moisture content. 5) Technique of measurement. The rougher and irregular the surface of granules, the higher the angle of repose.

21 Relationship between angle of repose and powder flow Exp. No. H (m) Mean θ = D(cm) tan θ θ Angle of repose θ More than 65 Powder flow Excellent Good Fair Passible Poor Very poor Very, very poor Comment: From the results and the table of the experiment, it was found that the angle of repose equals to.which means that the powder has flowability.

22 3) Measurement of bulk density(g/cm3) 1)Gently put 50 g powder into 100-ml graduated cylinder and record the volume(cm3) and calculate bulk density (D 0 ) before tapping (Fluffy bulk density). D ο = weight/volume before tapping =g/cm3 2) Tap the cylinder for minutes (till the powder volume become constant) and calculate D f (bulk density after tapping or equilibrium D f = weight (g)/ volume after tapping (cm3)= g/cm3). % compressibility(carr s index) = D f D ο / D f ) Х 100

23 Hausner factor = D f / D ο Hausner factor is related to inter-particle friction and so, predict powder flow. Powder flow Angle of repose θ Compressibilty index %(Carr's index) Hausner ratio Excellent Good Fair Passible Poor Very poor Very, very poor > 65 > 38 > 1.60

24 4) Particle size analysis 1) Using Sieves determine the provided powder (sod. Chloride, sod. Bicarbonate and calcium carbonate). 2) If the powder is more than 300 µm, the powder is course. 3) If the powder is between 300 and 180 µm, the powder is fine. 4) If the powder is less than 180 µm, the powder is very fine

25 5) Compressibilty 1) Compress the powder using single punch machine 2) If the powder is compressible, the powder is plastic. 3) If the powder is not compressible, the powder is elastic.