INTRODUCTION:

The preformulation studies we should know the properties of the drug, potency relative to the competitive products and the dosage form, literature search providing stability and decay data, the proposed route of drug administration, literature search regarding the formulation approaches, bioavailability, drug release and pharmacokinetics of chemically related drugs. It also includes preliminary investigations and molecular optimization by the drug should be tested to determine the magnitude of each Suspected problem area (Step I), if a deficiency is detected, a molecular modification should be done (Step II). To overcome this deficiency molecular modification is done be salts, prodrugs, solvates, polymorphs or even new analogues^[1].

The influence of polymorphism on physicochemical characteristics of solid drugs such as powder property, melting point, and enthalpy of fusion, dissolution behavior and stability are discussed in detail. Furthermore, a variety of differences in drug bioavailability and curative effect of polymorphs are also summarized and discussed^[2]. This has led to the increased attention being given to the physical properties of solids that contain a dosage form^[3].

Physicochemical Properties:

The ability of a chemical compound to elicit a pharmacological/therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts.

a. Investigation of physical and chemical properties of a drug substance – alone and or when combined with excipients is crucial during pre-formulation studies.

b. The development of any dosage form new drug, it is essential that certain fundamental physical and chemical properties of drug powder are determined.

c. This information may dictate many of subsequent event and approaches in formulation development.

d. The physicochemical properties are the first step in the rational development of a dosage form of a drug substance alone and when combined with excipients.

Types of physicochemical properties

A) Solubility related

B) Bulk related

C) Chemical

A) Solubility related:

1 Solubility

2 Dissolution

3 Partition coefficient

4 Common

5 PKa

B) Bulk related:

1 Flow properties

2 Density

3 Particle size

4 Surface area

5 Crystallinity

6 Polymorphism

7 Hygroscopy

8 Compressibility

9 Drug excipienent compatibility

C) Chemical related:

1 Decarboxylation

2 Racemization

3 Photolysis

4 Enzyme inhibition

5 Oxidation

6 Hydrolysis

7 Isomrisation

A. Solubility related:

1) Solubility:

Solubility is an important phenomenon in pharmaceutical sciences. It plays very effective and prominent role in the formulations of dosage form. Solubility of a compound in a particular solvent is defined as the concentrations of the solute in a saturated solution at a certain temperature. In another term it may be defined as the continuous interaction of two or more compounds to form homogeneous molecule dispersion. On the basis of solute and solvent present in the solution. Standard buffer solutions described in pharmacopoeia (B.P. 2003) ^[4] are considered appropriate for use in solubility studies.

Why to study solubility?:

Solubility is an essential and extensively studied preformulation parameter. Disturb the Stability of formulation Drug delivery. Such information is important to the formulator, for it enables him to select the best solvent medium for a drug, identify and overcome certain challenges that arise in the formulation of pharmaceutical solutions, and, furthermore, estimate the level of all known and significant impurities and contaminants in the drug molecule under evaluation.

Methods for determination of solubility and dissolution rate of sparingly soluble drugs

1. Shake-flask method can be used for almost all compounds. It’s precision and through put was proven greater the potentiometric method. Up to 20 compounds per week can be studied with one set-up. The miniaturized shake-flask method needs more drugs though to ensure equilibrium between solid and dissolved drug.

2. Semiautomated potentiometric acid/base titrations method is a very economical method and is able to create a ph/solubility profile with one single determination. Only 100 μg of poorly soluble compound is needed. The time required for a potentiometric titration vary depending on the compound, whereas the time consumption with a shake-flask method is fixed but overall it requires more time. However, this method is limited to ionizable compounds.

3. A computational screening model is used for the prediction of intrinsic solubility, which is based on lipophilicity and molecular surface areas.

Table no1: Determination of solubility and dissolution rate

Descriptive term	Parts of solvent required for 1 part of solute	G/l in water
Very soluble	≤1	≥1000
Freely soluble	1to 10	1000 to 100
Soluble	10 to 30	100 to 33
Sparingly soluble	30to 100	33 to 10
Slightly soluble	100 to 1000	10 to 1
Very slightly soluble	1000to 10000	1 to 0,1
Practically insoluble, or insoluble ≥	≥10000	≤0,1

Biopharmaceutical classification system based on solubility and permeability ^{[5, 6]}

Table no 2: Biopharmaceutical classification system

Class	Solubility\ permeability
Class I	High solubility High permeability
Class II	Low solubility High permeability
Class III	High solubility Low permeability
Class IV	Low solubility Low permeability

Factors affecting solubility Some of the methods to improve solubility of drugs

1) Temperature 1. Structure modification

2) Types of solute 2. Use of Solvent

3) Types of solvent 3. Employing surfactant

4) PH 4. Complicaxion

5) Particle size

6) Molecular structure

7) Common ion effect

8) Combined effect of solvent and PH

9) Effect of complex formation

10) Effect of wetting agent or surfactant

11) Effect of non electrode

2) Dissolution:

Dissolution is a process in which a solid substance solubilises in a given solvent i.e. mass transfer from the solid surface to the liquid phase. The dissolution rate is a measure of the actual release rate of the compound at the given particle size etc. in an aqueous media. Dissolution is a process by which a solid substance (drug) goes into the solution, that is, mass transfer of molecules from the solid surface to the liquid phase ^[7]. It often varies considerably with solid form, e.g. Particle size and shape Dissolution tests are used for:

Ensuring that production processes are under control.

USP Dissolution Apparatus:

1) Apparatus 1 - Basket (37⁰C)

2) Apparatus 2 - Paddle (37⁰C)

3) Apparatus 3 - Reciprocating Cylinder (37⁰C)

4) Apparatus 4 – Flow-Through Cell (37⁰C)

5) Apparatus 5 – Paddle over Disk (32⁰C),

6) Apparatus 6, Cylinder (32⁰C),

7) Apparatus 7, Reciprocating Holder

1) Apparatus 1 - Basket (37⁰C)- It comprises of borosilicate glass and holds a capasity of up to 1000ml. The shape is semi-hemespherical at the bottom while its shaft is made out of stainless stell.The shaft hold the cylinder basket it is usually refered to as rotating basket because it rotates smoothly and its rotating speed must be in form with the recommended USP the common speed limit is 100 rpm.It is used for capsules or tablet, suppositories,floating dosage form and delayed release.

2) Apparatus 2 - Paddle (37⁰C)- This apparatues specially made and it commes with a coated paddle that reduces the disturbance from the stirring apparently,it as a blade that comes in contact with the bottom of the shaft.the paddle apparatues is designed from stainless steel.it also has a platinum wire that protects the capsules from floatin.The paddle motor speed is usuallly at 40 and the paddle kept add at 37c.The paddle is kept in the position that specified in the current USP.It has a motor speed of 50rpm for capsule while 25rpm for suspension.

3) Apparatus 3 - Reciprocating Cylinder (37⁰c)- This dissolution apparatus is usually considered in a product development for controlled release prepration. The reasone for this is aid the release of product in GI tracts by exposing them to various physicochemical conditions and mechanical conditions.it is an a easy method for a drug testing and it does not pose any problem with the PH values of its solution.It is used for extended release,chewable tablets.

4) Apparatus 4 – Flow-Through Cell (37⁰c)- It is a made of two types which are the open system and the closed system.The open system has a fresh medium pumped through the cells and then the fractions received. The fraction are usually drawn every 30min.The dissolution test conducted with this apparatus should be conducted in the best sink condition available.The closed system on the other hand is where the medium is pumped into the circle but not replaced by a fresh medium.It is a normally used for drugs with a low dosage and a test is conducted in small volumes.The flow through the cell apparatus is designed like a reservoir and is a commonly used for implants.

5) Apparatus 5 – Paddle over Disk (32⁰c)- Transdermal Delivery System, use paddle and vessel from Apparatus 2 with a stainless steel disk assembly to hold the transdermal on the bottom of vessel.

6) Apparatus 6, Cylinder (32⁰c)- Transdermal Delivery System, use Apparatus 1 except replace the basket shaft with a stainless steel cylinder element.

7) Apparatus 7, Reciprocating Holde-or transdermal delivery systems and also a variety of dosage forms

Factor affecting dissolution process-

1 Factor relating to the physicochemical properties of drug

2 Factor related to drug product formulations

3 Factor related to the dissolution testing device centricity of agitating (stirring) element

4 Factors related to dissolution test parameters

5 Miscellaneous Factor

1. Factors relating to the physicochemical properties of the drug:^[8]

Solid-phase characteristics:

The solid-phase characteristics of drugs, such as amorphicity and crystallinity, have been shown to have a significant effect on the dissolution rate. Studies have demonstrated that the amorphous form of a drug usually exhibits greater solubility and higher dissolution rate as compared to that exhibited by the crystalline form.

Polymorphism the polymorphic forms of drugs have shown to influence changes in the solubilizing characteristics and thus the dissolution rate of the drug substance. Numerous reports have shown that polymorphism and the states of hydration, salvation, and/or complexation markedly influence the dissolution characteristics of the drug.

Coprecipitation and complexation Numerous reports have shown that polymorphism and the states of hydration, salvation, and/or complaxation markedly influence the dissolution characteristics of the drug.
Radical characteristic according to Nernst--Brunner theory, the dissolution rate is directly proportional to the surface area of the drug. Since the surface area increases with decreasing particle size, higher dissolution rates may be achieved through the reduction of particle size. This effect has been highlighted by the superior dissolution rate observed after micronization of certain sparingly soluble drugs as opposed to the regularly milled form.

2. Factors related to drug product formulation:

A variety of factors concerning the formulation of a drug product can directly influence the dissolution rate of the active ingredient contained within it. Once these factors are completely characterized, one can use this information to achieve custom-tailored drug dissolution profiles. This information is then employed in the development of optimally effective dosage forms.

Excipients and additives:

Most solid dosage forms incorporate more than one excipients for various purposes together with the active ingredient21 in the formulation. It has been shown that the dissolution rate of a pure drug can be altered significantly when mixed with various adjuncts. These adjuncts include diluents, binders, lubricants, granulating agents, disintegrates, and so on. In the following discussion we address the influence of excipients on the rate of dissolution of the active ingredient from a dosage form.

Particle size:

Several investigators have concluded that in most instances, reduction in particle size of drugs contained in tablets or capsules will enhance dissolution and absorption. This can most likely be attributed to the procedures22 employed in tablet production: that is, mixing the drug with usually hydrophilic diluents and subsequent granulation will result in a more hydrophilic surface, even for originally hydrophobic drug particles. Have extensively evaluated the effect of particle size on the dissolution rate of drug from granules and tablets.

Granulating agent and binder:

It has been reported by several investigators that binder and granulating agent incorporated in tablet formulation and other solid dosage forms can markedly influence the dissolution characteristics of the drug from the dosage form. Solving and finholt19 have shown that Phenobarbital tablet granulated with gelatin solution provide a faster dissolution rate in human gastric juice than do those prepared using sodium carboxy methylcellulose or polyethylene glycol6000 a binder.

Disintegrating agents:

Several reports have been published in the literature demonstrating the effect of various disintegrating agents on the dissolution rate of tablets27-29. It must be noted that the type and amount of disintegrating agent employed in the formulation significantly controls the overall rate of dissolution of the dosage form.

Lubricants:

Lubricants that are commonly incorporated in the formulation of solid dosage forms fall predominantly in the class of hydrophobic compounds. Consequently, the nature, quality, and quantity of the lubricant added can affect the dissolution rate. The effects of various lubricants on the dissolution rate of salicylic acid tablets were studied by levy and gumtow30. They concluded that magnesium stearate, a hydrophobic lubricant, tends to retard the dissolution rate of salicylic acid tablets, whereas sodium lauryl sulfate enhances dissolution, due to its hydrophilic character combined with surface activity, which increases the microenvironment ph surrounding the weak acid and increases wetting and better solvent penetration in to the tablets.

Interfacial tension between drug and dissolution medium:

The properties of the interface between the drug and the dissolution medium can become a deciding factor as far as dissolution rate is concerned. The characteristics can be modified by the addition of agent that acts at the interface.

Surfactant:
the drugs that are practically insoluble in aqueous medium (<0.01%) are of increasing therapeutic interest, particularly due to the problems associated with their bioavaibility when administered orally. Drugs with low solubilities when incorporated with surfactants can enhance their dissolution rate.

3. Factor related to the dissolution testing device centricity of agitating (stirring) element:

The current official compendium specifies that the stirring shaft must rotate smoothly without significant wobble. The lerrd significant gives the experimenter full right to ensure that such wobble does not significantly affect the dissolution rate.

Vibration:

The speed of the rotational device selected by official compendium is 100 rpm. Other speeds are specified for certain drugs. Precise speed control is best obtained with a synchronous motor that locks into line frequency25. Such motors are not only more rugged but are far from reliable. Periodic variations in rpm might result in possible disturbance in rotationala aceleration.

Flow pattern disturbances:

For dissolution-rate data to be reproducible and reliable, the flow pattern should be consistent from test to test. The geometry and alignment of the stirring device, external vibration, and rotational speed are some of the factors that can influence flow patterns. In 1978, drtl conducted an extensive examination of these factors and their influence on dissolution testing. They concluded that the geometry of the rotating paddle and/or basket, the flask dimensions, and the sampling positions can all introduce various types of flow patterns that can alter the dissolution characteristics of the drug product.

Sampling probes, position, and filters:

Large probe can affect the hydrodynamics of the system and therefore the dissolution rate of some dosage forms, causing results that differ from those obtained by manual sampling30-35. Usp states that samples should be removed at approximately half the distance from the bottom of the basket or paddle to the surface of the dissolution medium and not closer than 1 cm to the side of the flask. The choice of a filter should be preceded by an investigation of the adsorption characteristics of the drug and the particular filter material.

4. Factors related to dissolution test parameters:

Temperature:

USP specifics that the dissolution medium must be held at 37°c (0.5°). Although most commercial water baths can meet this standard of performance, failure to meet this requirement is not uncommon; it is often assumed that the water-bath temperature and the flask temperature are the same. Plastic flasks have a heat transfer coefficient approximately 3.5 times less than that of glass. As the temperature difference between the bath and the flask's medium is lowered, the amount of heat transferred into the flasks is reduced. It is vital to cover the flasks at least during dissolution testing. Since the drug solubility is temperature dependent, its careful control during the dissolution process is crucial. The effect of temperature variations of the dissolution medium depends mainly on the temperature-solubility curves of the drug and excipients in the formulation.

Dissolution medium:

The constituents, nature, and overall characteristics of the dissolution medium have a significant bearing on the dissolution performance of a drug substance. Also, selection of the proper dissolution medium for dissolution testing depends on the solubility of the drug as well as on economics and practicality. Factors such as dissolved gases, media ph, and viscosity of the medium have been shown to be significantly influential as far as dissolution rate is concerned.

Viscosity:

Dissolution rate decrease with increase viscosity of the dissolution medium; especially in the case of diffusion controlled dissolution process. Viscosity has very little effect on interfacial controlled dissolution process.

5. Miscellaneous factor Sorption:

The relative density of the tablets was found to decrease, resulting in increased disintegration time with increase in water sorption rate constants.

Humidity:

The relation to the dissolution rate of a drug substance, humidity is usually associated with storage effects. Moisture has been shown to influence the dissolution of many drugs from solid dosage forms.

Detection errors:

Analytical methods are checked carefully for each dissolution system. Extreme care must also be exercised when laboratory methods are introduced into quality control to ensure that no part of the equipment interferes with sensitive determinations.

3) Partition coefficient:

The ratio of the concentrations of a solute in two immiscible or slightly miscible liquids, or in two solids, when it is in equilibrium across the interface between them. Partition coefficient determination method Partition co-efficient is one of the Physico chemical parameter which influencing the drug Transport & drug distribution. The way in which the drug reaches the site of action from the site of application. Partition co-efficient is defined as equilibrium constant of drug concentration for a molecule in two phases.

Factors affecting Partition Co-efficient

1. pH

2. Co solvents

3. Surfactant

4. Complexation

— Partition Co-efficient is difficult to measure in living system.

— They are usually determined in vitro 1-octanol as a lipid phase and phosphate buffer of pH 7.4 as the aqueous phase.

— The Partition co-efficient, P is dimensionless and its logarithm, log P is widely used as the measure of lipophilicity.

— The log P is measured by the following methods.

1) Shake flask method

2) Chromatographic method

3) Spectroscopy method

Phenobarbitone has a high lipid/water partition coefficient of 5.9. Thiopentone sodium has a chloroform/water partition coefficient of about 100, so it is highly soluble in lipid.

Shake-flask method:

In order to determine a partition coefficient, equilibrium between all interacting components of the system must be achieved, and the concentrations of the substances dissolved in the two phases must be determined. A study of the literature on this subject indicates that several different techniques can be used to solve this problem, i.e. The thorough mixing of the two phases followed by their separation in order to determine the equilibrium concentration for the substance being examined.

4) Common ion effect:

Some of the salt will be precipitated until the ion product is equal to the solubility product. In short, the common ion effect is the suppression of the degree of dissociation of a weak electrolyte containing a common ion.

Example:

The solubility of insoluble substances can be decreased by the presence of a common ion. Agcl will be our example. Agcl is anionic substance and, when a tiny bit of it dissolves in solution, it dissociates 100%, into silver ions (ag⁺) and chloride ions (cl¯).

Affect the formulation of common ion effect:

The solubility of a sparingly soluble salt is reduced in a solution that contains an ion in common with that salt. For instance, the solubility of silver chloride in water is reduced if a solution of sodium chloride is added to a suspension of silver chloride in water. A practical example used vary widely in areas drawing drinking water from chalk or limestone aquifers is the addition of sodium carbonate to the raw water to reduce the hardness of the water. In the water treatment process, highly soluble sodium carbonate salt is added to precipitate out sparingly soluble calcium carbonate. The very pure and finely divided precipitate of calcium carbonate that is generated is a valuable by-product used in the manufacture of toothpaste. The salting out process used in the manufacture of soaps benefits from the common ion effect. Soaps are sodium salts of fatty acids. Addition of sodium chloride reduces the solubility of the soap salts. The soaps precipitate due to a combination of common ion effect and increased ionic strength. Sea, brackish and other waters that contain appreciable amount of na+ interfere with the normal behavior of soap because of common ion effect. In the presence of excess sodium ions the solubility of soap salts is reduced, making the soap less effective.

Buffering Effect:

A buffer solution contains an acid and its conjugate base or a base and its conjugate acid. Addition of the conjugate ion will result in a change of ph of the buffer solution. For example, if both sodium acetate and acetic acid are dissolved in the same solution they both dissociate and ionize to produce acetate ions. Sodium acetate is a strong electrolyte so it dissociates completely in solution. Acetic acid is a weak acid so it only ionizes slightly. According to le chatelier's principle, the addition of acetate ions from sodium acetate will suppress the ionization of acetic acid and shift its equilibrium to the left. Thus the percent dissociation of the acetic acid will decrease and the ph of the solution will increase. The ionization of an acid or a base is limited by the presence of its conjugate base or acid.

Nach3co2(s) → na+ (aq) + ch3co2− (aq)

Ch3co2h (aq) ⇌ h+ (aq) + ch3co2− (aq)

This will decrease the hydrogen ion concentration and thus the common-ion solution will be less acidic than a solution containing only acetic acid.

5) Pka ionization constant:

· Most of the drugs are either weak acids or base and can exist in either

· Ionised or unionized state.

· The ionization of the drug depends on its pKa and pH.

· The rate of drug absorption is directly proportional to the concentration of the drug at absorbable form but not the concentration of the drug at the absorption site.

· E.g.: Aspirin in stomach will get readily absorbed because it is in the un-ionized form (99%).

· E.g.; Barbituric acid is inactive because it is strong acid.

· 5, 5 disubstituted Barbituric acid has CNS depressant action because it is weak acid.

· E.g.: Phenytoin injection must be adjusted to PH12 with Sodium Hydroxide to obtain 99.98% of the drug in ionised form.

· Tropicamide eye drops, an anti cholinergic drug has a pk_a of 5.2 and the drug has to be buffered to pH 4 to obtain more than 90% ionization.

Methods to determine pka:

1) Potential electric method

2) Conductivity method

3) Dissolution rate method

4) Liquid-liquid partition method

CONCLUSION:

The physicochemical property is most important factor in solid dosage form Coues it’s occurring or chances to difficulties in formulation. The quality and curative effect of solid drugs, polymorphism of drug substances has been investigated in the pharmaceutical field for over 50 years. BCS relies on black and white definitions of solubility and permeability, are these definitions reliable or realistic, and There may be a risk of misclassification. The study of preformulation, characterization is important in solid dosage form.

ACKNOWLEDGEMENT:

Authors are highly Acknowledge the help of teaching staff of Rajarambapu College of Pharmacy, Kasegaon. For providing necessary information required for research work. Also we are highly Acknowledge the help and guidance of Dr M. M. Nitalikar.

REFERANCE:

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2. Jingkang Wang, The Effects of Polymorphism on Physicochemical Properties and Pharmacodynamics of Solid Drugs; Current Pharmaceutical Design; 2018; 24(21); 2375-2382.

3. Ahuja S and Scypinski S, Eds Handbook of Modern Pharmaceutical Analysis, Academic press, San Diego; 2001, volume 3 pp 85.

4. British Pharmacopoeia Electronic version: Appendix I D. Buffer Solutions. London: The Stationary Office; 2003.

5. Khan GM. Controlled release oral dosage forms: Some recent advances in matrix type drug delivery systems. The Science 2001; 1:350-54.

6. Lobenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm 2000; 50:3-12.

7. Sharma, J.L. Dictionary of Chemistry. New Delhi India: CBS Publishers and Distributors; 1997. p. 558-60.

8. Mitul Shah, Factor Affecting On Drug Dissolution Process; 2011.

Received on 20.12.2018 Accepted on 24.01.2019

Asian J. Pharm. Tech. 2019; 9 (1):53-59.

DOI: 10.5958/2231-5713.2019.00010.2