preformulation orals liquids and suspension

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2 Contents: Introduction Definition Aims of preformulation Preformulation of oral liquids Preformulation of suspensions


3 Introduction: The foundation of developing robust formulations Preformulation investigations are designed to deliver all necessary data (especially physicochemical, biopharmaceutical properties of drug substances, excipients and packaging materials) which may influence 1.Formulation design 2.Biopharmaceutical properties of the resulting product 3.Packaging of the product (stability)


4 Definition: Preformulation can be defined as numerous investigations on drug substances in order to produce useful information for subsequent formulation of the physicochemically stable and biopharmaceutically suitable drug dosage form.

Aims of preformulation:: 

5 Aims of preformulation: Learning before Doing–Develop basic knowledge . Choose the correct form of the drug substance. Evaluate physical properties of drug. Generate thorough understanding of material stability. To understand the drug compatibility with drug excipients. Provide guidelines for formulator, analyst, and medicinal chemist. To understand degradation mechanism of drug.

In case of Oral liquids:: 

6 In case of Oral liquids: These are the homogenous liquid preparations containing one or more dissolved ingredients & are used as variety of dosage forms.


7 Parameters: The parameters mainly considered under oral liquids are: Solubility Stability


8 Solubility: To form homogenous liquid preparations the drug should be completely soluble in solvent. Solubility : “maximum extent of solute that dissolves in given amount of solvent.”

Factors that should be considered under solubility:: 

9 Factors that should be considered under solubility: Ionization constant (pKa)/ pH dependency Partition coefficient Common ion-effect Solubilization

Ionization constant (pKa): : 

10 Ionization constant (pKa): The Henderson–Hasselbalch  equation provides an estimate of the ionized and un-ionized drug concentration at a particular pH. - For acidic drugs, pH = pKa + log(ionized drug)/un-ionized drug) - For basic drugs, pH = pka + log(unionized drug/ionized drug) - Buffers, temperature, ionic strength and cosolvent can affect the pka value.

Partition coefficient:: 

11 Partition coefficient: Partition coefficient is defined as the ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium. P O/W = C oil /C water Thus in any formulation, the lipophilic /hydrophilic balance should always be maintained to yield a perfect formulation.


12 Importance: Partition coefficient is mainly required: To determine hydrophilic and lipophilic nature of drug substance To determine bioavailability of drug

Common ion effect:: 

13 Common ion effect: Common interaction with solvent which is often overlooked is common ion effect. The addition of common ion often reduces the solubility of lightly soluble electrolytes. This is known as salting out.


14 Solubilization: It is spontaneous passage of poorly water-soluble solute molecule into aqueous solution to form thermodynamically stable solution.

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15 Methods to enhance solubility: Co-solvency Complexation Salt formation Surfactant Temperature pH solubility profile


16 Stability: The main objective of this is identification of condition necessary to form stable solution. 1.Chemical stability 2.Physical stability

These study includes,: 

These study includes , pH-profile Light Temperature Oxygen

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18 The drug is exposed to all above parameters at extreme condition. It helps to study degradation mechanism that is degradation due to hydrolysis, oxidation etc.

In case of suspensions:: 

19 In case of suspensions: It is the type of disperse system in which a substance is distributed or suspended in particular form throughout the another. There are two types of suspensions: coarse suspension colloidal suspension

Ideal characteristics of suspension:: 

20 Ideal characteristics of suspension: It must remain homogeneous for at least period of shaking the container & removing required dose. Sediment produced on storage must be easily resuspended by use of moderate agitation. Suspension may be required to be thickened to reduce rate of settling of particle. The viscosity must not be so high that removal or transfer is difficult. Suspended particle should be small & uniformly sized to give smooth product, free from gritty texture.


21 Parameters: Parameter mainly includes: Bulk properties Wetting Rheology Solubility Stability/Sedimentation

Bulk properties:: 

22 Bulk properties: Particle size Polymorphism Crystal properties

Particle size:: 

23 Particle size: Particle size mainly affect stability of suspension. Rate of sedimentation of suspended particles can be retarded by reduction in its size. Large particles if greater than about 5 μ m diameter, will also impart gritty texture to the product.


24 Polymorphism: Polymorphs are the forms of compounds which are present in two or more crystalline forms with different internal lattices. These are having same molecular weight but different physicochemical, pharmacological and toxicological properties.


25 Polymorphs: - low energy - low solubility - low rate of dissolution Stable Metastable - high energy - high solubility - high rate of dissolution Polymorphs

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26 Suspension system should never be made with metastable form as metastable form is more soluble than stable form.

Crystal properties:: 

27 Crystal properties: Crystal habit is defined as outward appearance of agglomeration of crystals. It is having great importance in suspension redispersibility, sedimentation, physical stability, appearance.


28 Wetting: First requirement to produce pharmaceutical suspension is to achieve adequate wetting of solid particle by liquid vehicle. To ensure adequate wetting interfacial tension between solid and liquid must be reduced so that absorbed air is displaced from solid surfaces by liquid.

Wetting agents:: 

29 Wetting agents: Surfactants Hydrophilic colloids Flocculating agents Polymers


30 Surfactants: Surfactants possess some distinct region of lipophilic & hydrophilic characters. Surfactants possessing HLB value between about 7 to 9 would be suitable for use as wetting agents.

Hydrophilic colloids:: 

Hydrophilic colloids: These hydrophilic colloids behave as protective colloids by coating the solid hydrophobic particles by multimolecular layer. It imparts hydrophilic characters to the solid.

Flocculating agents:: 

Flocculating agents: Deflocculating suspension: It consists of disperse particles that remain as discrete units. Flocculating suspension: It is made up of many floccules. The floccule consists of many individual particles. Flocculating agents are used to convert deflocculating suspension to flocculating suspension.


Polymers: Polymers are used to control degree of flocculation. Their linear branched chain molecules form the network within the system & become adsorbed on surface of dispersed particles. Thus holding them in flocculated state.


34 Rheology: An ideal suspension would exhibit high apparent viscosity at low rates of shear so that on storage, suspended particles would either settle very slowly or preferably remain suspended.

Viscosity modifiers:: 

35 Viscosity modifiers: Viscosity modifiers are mainly used to maintain reology. These mainly includes: Polysaccharides Cellulose Silicates


36 Solubility: In case of suspension, it has to be considered that reduced solubility is desired. Selection of vehicle is necessary to prevent crystallization.


37 Stability/Sedimentation: Stability of suspensions is controlled by means of adequate knowledge of nature and mechanism of interaction between components in it as well as temperature condition, pH etc. Oswalds ripening Degree of flocculation

Oswalds ripening:: 

Oswalds ripening: The formation of large particles at the expense of smaller particles is known as “Oswalds ripening”. Temperature fluctuation is one factor that promotes Oswalds ripening.

Degree of flocculation:: 

Degree of flocculation: If the suspension is deflocculated the dispersed particles remain as discrete units & since the rate of sedimentation depends on the size of each unit, settling will be slow. The slow rate of settling prevents the entrapment of liquid within the sediment which thus becomes compacted & can be very difficult to disperse. It is known as caking .

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In case of flocculated system, aggregation of particles will lead to rapid rate of sedimentation . But it get easily dispersed, so flocculated systems are usually preferred. A deflocculated system with a sufficiently high viscosity can be used.

Factors affecting stability:: 

41 Factors affecting stability: Particle size Temperature Viscosity


42 REFERENCES: Howard C, Ansel L, AllenJr V, Popovich NG. Pharmaceutical dosage forms and drug delivery systems, published by Lippincott William & Wilkins, 6 th ed ,p no. 103. Aulton ME, WellsJI. Pharmaceutics-The science of dosage form design Vallabh prakashan.p no.223-238,242-246,269-280. Niazi SK. Handbook of Preformulation, Chemical Biological and Botanical Drugs. published by informa healthcare p no.241,262-263,272-273.

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Rhodes CT. Preformulation In: Banker R, Rhodes CT. Modern Pharmaceutics,3 rd ed vol.702 p no.213. Fiese EF, Hagen TA. Preformulation. In:Lachman L, Herbert A, Lieberman. The Theory and Practice of Industrial Pharmacy. Varghese publication,3 rd ed,p no.171-192,457-465,472,480-490.

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