Essay: ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

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CHAPTER -1 INTRODUCTION

SMRITI COLLEGE OF PHARMACEUTICAL EDUCATION, INDORE PAGE 1

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

Introduction –

Poorly water soluble drugs are concerned with the slow drug absorption and have insufficient and variable bioavailability, 40% of a raw drug had been identified which are poorly water soluble. Founded on the permeability and solubility according to biopharmaceutical classification system drugs are categorized on two classes, grade II and Class IV. The biopharmaceutical classification Class II drugs show high permeability and low solubility that indicates that drugs are poorly water soluble. Therefore, increase the solubility also increases the bioavailability of therapeutic agents. The two key parameters permeability and solubility play an important role in the absorption of drugs. Solubility is the important phenomenon in the pharmaceutical dosage formulation. 1

Table No. 1 The biopharmaceutical classification are- 2

Class I

Solubility Permeability

Class II

Solubility Permeability

Class III

Solubility Permeability

Class IV

Solubility Permeability

1.1 Definition- Solubility is defined as, ability of the solid to get dissolved in a particular solvent. IUPAC defines solubility it is the analytical composition of a saturated solution expressed as a proportion of a solute in a solvent. Solubility may be maintained in units of concentration, morality, mole fraction, mole ratio, and other units.

The pharmacopeia reports the solubility in term of number of millimetres of solvent required to dissolve1 gm of solute. The descriptive term is given as-

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

1.2 Important of solubility –

Table No. 2 Descriptive term defines

S. No

Definition

Parts of solvent require for 1part of solute

1

Very soluble `

Less than 1

2

Freely soluble

1 to10

3

Soluble

10 to 30

4

Sparingly soluble

30 to 100

5

Slightly soluble

100 to 1000

6

Very slightly soluble

1000 to 10,000

7

Insoluble

More than10,000

Solubility of the drug is depending upon the therapeutic effectiveness. The many of the drugs are taken by oral routes and their oral bioavailability highly depended on the solubility. 40% of the drugs are poorly water soluble therefore they have, the slower drug absorption leads to insufficient and variable bioavailability. 3

1.3 Solubilization Process: -The process of solubilization contains three steps-

1. The separation of solvent molecules, and provides space for solute molecules.

2. Breaking down of inter molecular ions of solute molecules.

3. Interaction between solvent molecules and solute molecules.

3

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

Fig.1 Process of Solubilization 4

1.4 Factors affecting solubility:-

Various components which affect the solubility are-

 Particle size

 Temperature

 Pressure

 Molecular size

 Nature of solute and solvent

1.4.1 Particle Size – Solubility increases if the solute particle size is small. Because the atom size is of solute is small their surface area is more. The bigger surface area has more concentration of the solute.

1.4.2 Temperature – Generally, increase the temperature of the solution also increases the solubility of solute. A few solid solute, are less soluble in warmer solution.

1.4.3 Pressure – For the solute (solid and liquid) changes in pressure practically not affects the solubility. For gaseous solute an increase the pressure also increases the solubility, and decrease the pressure as well as decrease the solubility.

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

1.4.4 Molecular Size – When the molecule causes a higher molecular weight and size that decrease the solubility. Because large molecule is more difficult to surround solvent in order to swat the substance.

1.4.5 Nature of Solute and Solvent – The nature of solute and solvent depend on the concentration of solute in a specific quantity of solvent at a specific temperature. 5

1.5 TECHNIQUES OF SOLUBILIZATION:-

Various techniques of solubility enhancement

 Physical Modifications – Particle size reduction like micronization and nanosuspension

drug dispersion in carriers like eutectic mixtures, solid dispersions.

 Chemical Modifications – Change of pH, use of buffer, derivatization, complexation,

and salt formation.

 Miscellaneous Methods – Supercritical fluid process, use of adjuvant like surfactant,

solubilizers, co solvency, hydrotherapy, and novel excipients. 6

1.5.1.1 Particle Size Reduction- In this method, particle size was reduced and their surface area was increased. Larger surface area creates greater interaction with solvent to cause solubility.

 Micronization- Micronization is a method of particle size reduction, in this method the

particle size of the substance is reduced and increases the absorption rate due to the higher surface area. In this process the particle size of solid drug particles is reduced from 1-10 microns by spray drying or other attrition method (jet mill). Micronization also called micro-milling.

o Jet milling – A fluid jet mill uses the energy of the fluid (high pressure air) two ultra fines grinding of pharmaceutical powders. It has several advantages of being a dry process, size reduction of micron sized particle. The increase in dissolution behavior is attributed to increased particle surface area.

o Ball milling- A ball mill usually a cylindrical crushing device that is used for grinding of pharmaceutical powders by rotation around a horizontal axis. A Ball milling technique used for size reduction of amorphous form.

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

 Nanonization – In this method drug powder is converted into the nanocrystal and their size rang 200-600 nm. Through the process of nanonization result increases the solubility and it also decreases the side effects. There are many techniques which are used in nanonization such as-

o Pearl milling

o Homonization in water

o Homonization in non aqueous media or in water with water miscible liquid. 7

1.5.1.2

1.5.1.3

1.5.1.4

1.5.1.5

1.5.1.6

Use of Precipitation Inhibitors – A significant enhances the solubility of free drug concentration above equilibrium results super saturation, which get drug precipitation and crystallization. It is inhibited by inert polymer such as polyethylene glycol, poly vinyl pyridine, hydroxypolyvinylpyridine. 8

Gas Antisolvent Recrystallization- It is well known technique for enhancing the solubility of poorly water soluble drugs. In this method a particular solute can be added to the solution to get precipitate out. It is called salting out and used for crystallization purposes. 9

Supercritical Fluid Recrystallization- A supercritical fluid is defined as, it is a dense non condensable flu
id whose temperature and pressure are greater than its critical

temperature and critical fluid assume the property of liquid and gas. It is applied in pharmaceutical industries and food industries. Commonly used supercritical fluid carbon dioxide, ethanol, ammonia and water, ethylene, propylene and propane. 10

Alteration of pH – Alteration of pH is attained in two ways- a) addition of buffer,

b) Salt formation. Poorly water soluble drugs are difficult to dissolution by changes in pH can increase the solubility of the drug and buffer solution is also used to increase the solubility of the drug. 11

Solid Solution- A solid solution is called the binary system because of a solid solute molecularly dispersed in a solid solvent. Hence the two compartments crystallize

together in a homogenous one phase system; solid solutions are also known as molecular dispersion or mixed crystals. Because the reduction of particle size of molecular level

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

1.5.1.7

shows greater water solubility and also higher dissolution than eutectics and solid dispersion. Solid solution is generally made by fusion method. 11

Eutectic Mixture – This system is prepared by fusion method. In this mixture two or more compounds which are not interacting or form a new chemical compound. Eutectic mixture is formed fused melt of solute solvent show complete miscibility but negligible solid solubility. 12

1.5.1.8 Co-Solvent – Co solvent system is used to increase the solubility of drugs. The co- solvency method is used to increase the solubility by adding water miscible solvent in which the drug is easily soluble. This process also called as co-solvency. Co-solvent works reducing the interfacial tension between solvent and solute. Many solvent are glycerin, propylene glycol, dimethylsulfoxide, ethanol and N, N dimethylformamide etc. The co-solvents are having hydrogen acceptor or donor groups with a small hydrocarbon region. 13

1.5.1.9 Inclusion Complexation- Inclusion complexation techniques are definitely enhanced solubility and dissolution rate of the drug. Inclusion complexation is formed when a non polar molecule or non polar region of one molecule (known as a guest) inserted into the cavity of other molecule called as (host). The most common complexion agent is used in this technique such as, β-Cyclodextrins, caffeine, urea, polyethylene glycol, N methylglucamide. 14

1.5.1.10 Hydrotropy- This process is firstly discovered by Neuberg in 1916. This process is defined as it is solubilization process whereby the addition of large amount of secondary solute increases the solubility of another solute. Different typed of hydrotropic agent are used such as urea, sodium benzoate, sodium salicylate, nicotinamide, sodium citrate and sodium acetate. This method involves two processes are. Salting in and salting out. 1. Hydrotropic agents and solute that increase the solubility of any solvent is called salting in. 2. Hydrotropic agents and solute that decrease the solubility is called as salting out. The main advantage of this technique is that it only required drug mixing with the hydrotropic solution. 15

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

1.5.1.11 Mixed Hydrotropy- In this method blends of hydrotropes are used. This Method is safe, cost-effective and accurate. In this method combination of hydrotropes are used. The Combination of hydrotropes gives the synergistic effect of poorly aqueous soluble drugs. Application of mixed hydrotropy is the use of hydrotropic agent as a permeation enhancer. 16

1.5.1.12 Co-Crystallization- It is referred to as molecular complexes. Co-crystallization is defined as crystalline material that consists of two or more molecules (and electrically neutral) species held together by non-covalent forces. Only three of the co-crystallizing agents are classified and generally recognized as safe. It includes saccharin, nicotinamide and acetic acid limiting the pharmaceutical application. Co-crystallization between two active pharmaceutical ingredients has also been reported such as aspirin or acetaminophen. 17

1.5.1.13 Use of Salt Form- Salt increases the solubility of poorly water soluble drugs. It is an effective method for parenteral preparation and also solid dosage form. During 12 years Food and Drug Administration approved approximately 300 new chemical entities, whereas 120 are available in salt form. Out of this 101 salts approved for basic drugs and 54 salts for acidic drugs. The dissolution rate also increases by salt form. 18

1.5.1.14 Liquid solid Compacts – Liquid solid compact formulation is a method which is used for hydrophobic drugs dissolved in non-volatile, nontoxic, hydrophilic solvents such as, polyethylene glycol, glycerine, or polysorbate-80 mixed with carriers like MCC, lactose, or polyvinyl pyrrolidone- K30 using slilica as a coating material in optimized formulation and finally compressed into a compact mass. In recent years, this technique was used to enhance the dissolution rate of many drugs. 19

1.5.1.15 Use of Surfactant- Surfactant is used for the solubility enhancer. Surfactant increases dissolution rate as well as permeability of drug. Several types of surfactant are used like ionic surfactant (sodium dodecylsulphate), non-ionic surfactant, cationic surfactant (cetyltrimethylammonium bromide) Ionic surfactant give more effect than non-ionic surfactant. Solubility found much higher ionic surfactant than cationic surfactant. 20

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

1.5.1.16 Solvent Deposition- In this method, poorly water soluble drugs are dissolved in organic solvent and deposited on the inert, solid and hydrophilic matrix. This matrix is made of starch and microcrystalline cellulose by evaporation of solvent. 21

1.5.1.17 Spray Freezing into liquid and lyphophilization – In this technique involves the atomization of an aqueous, organic, co solvent, solution, aqueous organic emulsion and suspension containing drug and pharmaceutical excipients directly into compressed gas. The dissolution rate of spray freezing liquid is enhanced and also has excellent wettability. 22

1.5.1.18 Solubilizing Agents – The solubility of poorly soluble drug can also be improved by various solubilizing materials. PEG400 is improving the solubility of hydrochlorothiazide 85. Modified gum karaya recently developed excipients were evaluated as carrier for dissolution enhancement of poorly soluble drugs. 23

1.5.1.19 Solid Dispersion- The solid dispersion was originally proposed by Sekiguchi and Obi, in 1960. Solid dispersion is a usable method to enhance the solubility of poorly water soluble drugs. It is useful in pharmaceutical industry increase dissolution of the drug and also increases the therapeutic efficacy.

1.6 Definition – Solid dispersion defined as, it is the science of dispersing one or more active ingredients in the matrix in solid state in order to achieve an increased dissolution rate. The most commonly used carries for solid dispersion are polyvinyl pyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), Plasdone- S630. Surfactants like Tween-80, Docusate sodium, Myrj-52, Pluronic-F68, and sodium lauryl sulphate (SLS). In this method, poorly soluble drugs are dispersed in hydrophilic matrix which increases the solubility and dissolution of drugs. Various techniques are used to enhance the solubility by solid dispersion are –

 Fusion Method / Melting Method- In this method the carrier is heated at temperature of low melting point and drug is incorporated in this matrix. After this cool at room temperature with constant stirring. This method is used to release the drug under controlled manner.

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

 Solvent Method- In this method drug and carrier is dissolved in suitable hydro alcoholic solvent. This solvent is evaporated at elevated temperature. Solvent is removed and resulted solid residue is obtained.

 Hot Melt Extrusion- This process is generally used in the polymer industry, but Speiser and Huttenrach were the first persons who use this technology for pharmaceutical purpose. In this hot melt extrusion the mixture of drug and carrier carry through heated screw, it is transformed into fluid like structure. In this state homogeneous mixing is done by high shear extruder. The main advantage of hot melt extruder is that the drug and carrier are melted at elevated temperature for 1 minute, which enables drug thermo labile to be proceeding. 23

1.6.1 Types of Solid Dispersion- Three types of solid dispersion are –

 Binary solid dispersion – It consists of the drug and carrier as a polymer.

 Ternary solid dispersion – It consists of the drug, polymeric carrier and a surfactant.

 Surface solid dispersion – surface solid dispersion is prepared by using the polymers

such PVP, PEG and polyvinyl pyrrolidone – vinyl acetate as a copolymer. 23

1.6.2 Classification of Solid Dispersion – solid dispersion are classified into four generations-

 First generation – First generation solid dispersion is crystalline solid dispersion. In

crystalline solid dispersion, a crystalline drug is dispersed within a crystalline carrier forming a eutectic or monotectic mixture. Example of crystalline carrier is urea, sugars and organic acids.

 Second generation – Second generation solid dispersion contains amorphous carriers, which are mostly polymers. Amorphous solid dispersion classified as amorphous solid solution and amorphous solid suspension according to the physical state of drug. Example – providone (PVP) and polyethylene glycol (PEG), hydroxypolymethylcellulose (HPMC) and starch derivative.

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

 Third generation- In third generation solid dispersion the surface active agents or self emulsifiers are used as a carriers or additives and show significant improvement. Example surface active self emulsifier is poloxamer 408 and tween 80.

 Fourth generation –The fourth generation solid dispersion is controlled release solid dispersion containing poorly water- soluble drugs with short biological half life. Example eudragit poly ethylene oxide and carpool. 24

1.6.3 Advantages of Solid Dispersion –

    

It improved wettabilitys that result in increased solubility.

Particle having higher porosity. Increase porosity also increase drug release profile. Amorphous status of drug leads to increase drug solubility and increase drug profile.

Increase drug solubility and dissolution rate that reduced pre-systemic metabolism. Solid dispersion technique used to reduce the particle size because small particle size increases large surface area. Large surface area increase dissolution rate and improved bioavailability. 25

1.6.4 Limitation of Solid Dispersion-

 Moisture and temperature may affect physical characteristics of solid dispersion.  Stability problem of drug and vehicle may occur.

 Large amount of carrier is required to achieve good dissolution.

 Method used for the formulation is expansive.

 Large amount of carrier is required to achieve good dissolution. 25

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

CHAPTER-2

RESEARCH ENVISAGED AND OBJECTIVE

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE 3.2 Research Envisaged-

 The majority of pharmaceutical compounds are poorly water soluble and new bioactive compounds that result from high-throughput screening programs tend to exhibit low solubility in water.

 Such compounds may exhibit insufficient dissolution throughout the gastrointestinal tract and therefore fail to achieve superior systemic exposure after oral administration. Today, failing bioavailability is one of the main reasons for abandoning innovative oral drug candidates.

 Etoposide an anticancer drug and is sparingly soluble in water.

 Etoposide is one of the commonly used drugs for the treatment of chemotherapy of cancer.

 Etoposide is a poorly water soluble drug (0.0008mg/ml) as per USP due to its poor aqueous solubility, etoposide has poor bioavailability and dissolution related problem.

 Etoposide has variable oral bioavailability ranging from 24-74%. Hence it was planned to increase solubility using solid dispersion technique.

Objective – The purpose of present study to enhance the aqueous solubility of poorly water soluble etoposide drug using solid dispersion technique.

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

CHAPTER- 3 REVIEW OF LITERATURE

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

Saripilli R et al, 26 (2016) reviewed on solid dispersions an evergreen solubility enhancement technique for hydrophobic drugs. They concluded solid dispersion is most promising technique. This method used to overcome the problem of poorly aqueous soluble drugs. They showed basis concept of solid dispersion, its advantages and disadvantages, their types and different method of preparation. They reviewed that solubility of drug molecule can be increased by modification of physiochemical properties of drug substance. They also discussed various methods used in solid dispersion to increase the solubility. They also concluded the researchers used different polymers to enhance solubility.

Sultana S and Saifuddin A H M 27(2016) reviewed on solid dispersion technique which widely used in pharmaceutical industries. Solid dispersion method extremely helps improving the dissolution property of low aqueous solubility of drugs. Their article reviewed on different type of solid dispersion technique, classifications, advantages, criticisms and current industrial applications. They also showed future treads of solid dispersion. They also discussed their review on various formulations which are marketed by solid dispersion technology.

Thakre N et al, 28(2016) worked on solubility of ezetimib drug and there result show increased the solubility and bioavailability of the drug. In their work there was no interaction found between drug and carrier and got thermo gram of polymer that indicates the formation of complexes. They also show powder x-ray diffraction was no sharp line peak because of conversion of solid form crystalline to amorphous form. Formation of Solid dispersion with PEG6000 and PVP K30 gave better result and increase the rate of dissolution. They show Koresmeyer peppas mode, it is best method for the release mechanism of drug from solid dispersion. They concluded that the two poly mers was used which is suitable for preparation of the solid dispersion that increase the solubility as well as bioavailability.

Gorniak et al, 29(2016) studied about physiochemical studied about physiochemical and dissolution study of ketoconazole – Pluronic F-127 Solid dispersions. They prepared solid dispersion of ketoconazole with Pluronic F-17by kneading and fusion method as compared to drug in pure form. They studied physiochemical properties of resultant dispersion by DSC, PXRD and FT-IR techniques and intrinsic dissolution profiles of th
ese formulations were

ENHANCEMENT OF AQUEOUS SOLUBILITY OF ETOPOSIDE USING SOLID DISPERSION TECHNIQUE

evaluated. On basis of DSC, XRD and FT-IR studies, they concluded that there is lack of drug- polymer interaction which was stated. They stated the ketoconazole enhancement by dissolution rate in 0.5% SLS in compared to that of pure drug is observed for resultant solid dispersion.

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