Quality control tests for topical preparations

Under the guidance of- Presented by-Mrs Indira Priyadarshini, M.pharm, Bhavana.G.(Y15MPh223) Assistant Professor, I/II M.pharm Dept. Pharm. Analysis

INTRODUCTIONDrug products topically administered via the

skin fall into two general categories, those applied for local action and those for systemic effects after absorption through the skin into the blood circulation.

Local actions include those at or on the surface of the skin, Common products in the former category include creams, gels, ointments, pastes, suspensions, lotions, foams, sprays, aerosols, and solutions.Creams, ointments, and gels generally are

referred to as semisolid dosage forms.

The most common drug products applied to the skin for systemic effects are referred to as self adhering transdermal drug delivery systems (TDS) or transdermal patches.

Functions of Dermatologicals• Protect injured areas from the

environment• Provide skin hydration (emollient)• Vehicle for medication transport

Creams, gels, ointments, pastes etc. Come under the category of semi solid dosage forms.

DEFINITION OF SEMI SOLID DOSAGE FORMS Semi solid pharmaceutical system comprise a

body of product ,which when applied to skin or accessible mucous membranes tends to alleviate or treat a pathological condition or other protection against harmful environment.

Ideal properties of Semi solid dosage form

Application propertiesa.Easy applicable with efficient

drug releaseb.High aqueous washability

Physical propertiesa)Smooth textureb)Elegant in

appearancec) Non dehydratingd)Non grittye)Non greasy and non

stainingf) Non hygroscopic

Physiological properties

a)Non irritatingb)Do not alter

membrane functionc) Miscible with skin

secretion

CLASSIFICATION

OINTMENTS• Ointments are homogenous, translucent,

viscous, semi solid preparation intended for external application to skin or mucous membranes. Ointment may be medicated or not..

Applied to mucous membrane or skin

Uses • Emollient• Application for active ingredients to the

skin• Occlusive

IDEAL PROPERTIES OF A BASE

• They should be: Compatible with skin ph. and drug Inert ,non irritating and non sensitizing Good solvent and/or emulsifying agent Emollient , protective , non greasy and

easily removable Release medicaments easily at the

site of administration Pharmaceutical elegant and possess

good stability.

OINTMENT BASES

OLEAGINOUS BASES

Examples:Hydrocarbon

s Animal

fats/vegetable oils White

petrolatumWhite

ointment

WATER SOLUBLE BASES

Examples:Polyethylene

Glycol Ointment,Biozyme

Ointment, Desenex

Ointment.

ABSORBTION BASES

EMULSION BASES

Examples:Hydrophilic petrolatumAquaphorAquabase

OINTMENTS

WATER IN OIL

OIL IN WATER

Oleaginous Bases

Absorption Bases

Water/Oil Emulsion

Bases

Oil/Water Emulsion

Bases

Water-miscible

Bases

Composition oleaginous compounds (water insoluble

hydrophobic oils and fats)

oleaginous base + w/o surfactant

oleaginous base + water (< 45% w/w)

+ w/o surfactant (HLB <8)

oleaginous base + water (> 45% w/w)

+ o/w surfactant (HLB >9)

Polyethylene Glycols (PEGs)

Wash ability Non-washable Non-washable non- or poorly washable

washable washable

Stability oils poor; hydrocarbons better

oils poor; hydrocarbons

better

unstable, especially alkali

soaps and natural colloids

unstable, especially alkali

soaps.

stable

Uses Protectants, émollients.

protectants, emollients, vehicles for

aqueous solutions.

emollients, cleansing creams, vehicles for solid,

liquid, or non-hydrolysable drugs

emollients, vehicles for solid,

liquid, or non-hydrolysable drugs

drug vehicles

Examples White Petrolatum, White Ointment

Hydrophilic Petrolatum,

Anhydrous Lanolin

Cold Cream type, Hydrous Lanolin,

Rose Water Ointment

Hydrophilic Ointment.

PEG Ointment, Poly-base.

Ointment Preparation• Incorporation: components are mixed until a uniform

preparation is attained.• Mortar/Pestle, Ointment Mill• Fusion: All components are combined by being melted

together and cooled with constant stirring until congealed.

-- High melting temperature bases such as beeswax, paraffin, stearyl alcohol.

Preservatives • Some bases , although, resist microbial attack but

because of their high water content, it require an anti microbial preservative.

Commonly used preservative include: Methyl hydroxy benzoate, Propyl hydroxy benzoate, Chlorocresol

CREAMSViscous semisolid preparations meant for

external use. They contain water soluble base which are easily removed from the skin.

TYPESAqueous creamsOily creams

Aqueous creams: These are O/W type. These are again divided into 3 types based on emulsifying agent.(a)Anionic emulsifying wax creams: These are

prepared by fusion method. The wax and oily ingredients are melted and cooled at 60°C.

(b)Cationic emulsifying wax creams: These are made as that of Anionic emulsifying wax creams. Ex: Cetrimide, Cetostearyl alcohol.

(c)Non ionic emulsifying wax creams: Similar to above. Ex: Polysorbates, Sorbitan esters.

Oily creams: These are W/O type. These are again divided into 2 types based on emulsifying agent.(d)Sterol creams: Here wool-fat is used as

emulsifying agent.(e)Soap creams: Tri-ethanolamine soap, calcium

soap are used as emulsifying agents.

PASTES • These are semisolid preparations intended for

external application to the skin. These don’t melt at ordinary temperature and form a protective coating over the area they are applied.

USES: 1. Antiseptic2. ProtectiveBASES USED FOR PASTESHYDROCARBON BASES Ex: Liquid paraffin, Soft paraffin.WATER MISIBLE BASES Ex: Glycerine. WATER SOLUBLE BASES Ex: Polyethylene glycols.

METHOD OF PREPARATION OF PASTES1. TRITURATION METHOD: This is used for

bases which is liquid or semi solid.2. FUSION METHOD: This is used for bases

which is solid or semi solid.

JELLIESThese are transparent, translucent non-greasy semi solid preparations meant for external application to the skin or mucous membrane.EX: Tragacanth, Pectin, Sodium alginates etc..Types of jelliesMEDICATED JELLIESLUBRICATING JELLIESMISCELLANEOUS JELLIESFormulations of jelliesGelling agents: usually organic hydrocollides. Example : tragacanth, sodium alginate, pectin, gelatin, cellulose derivatives

TRANSDERMAL PREPARATIONS• Designed to support the passage of drug

substances from the surface of the skin, through its various layers, and even into the systemic circulation.

Advantage of TDDS over other delivery systems : is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. Disadvantage: is that skin has very effective barrier so small molecules which can easily penetrate are used.

• ADVANTAGES Self administration is possible with these system. The drug input can be terminated at any point of

time by removing transdermal patch.Allows effective use of drugs with short biological

half-lifeAllow administration of drugs with narrow therapeutic

windowProvides controlled plasma level of very potent drugsDrug input can be promptly interrupted when toxicity

occurs• DISADVANTAGES: Drug or drug formulation may cause skin irritation or sensitization. Uncomfortable to wear . May not be economical.

mechanism

The common ingredients which are used for the preparation of TDDS are as follows. 1. Drug: Drug is in direct contact with release liner. Ex:

Nicotine, Methotrexate.2. Liners: Protects the patch during storage. Ex: polyester

film.3. Adhesive: Serves to adhere the patch to the skin for

systemic delivery of drug. Ex: Acrylates, Poly-iso-butylene, Silicones.

4. Permeation enhancers: Controls the Release of the drug. Ex: Terpenes, Terpenoids. Solvents like alcohol, Ethanol, Methanol etc.

5. Backing layer: Protect patch from outer environment. Ex: Cellulose derivatives, poly vinyl alcohol, Polypropylene Silicon rubber.

6. Polymer matrix: The polymer controls the release of the drug from the device. Ex: Natural polymers, Synthetic Elastomers, Synthetic Polymers

• Ideal properties of polymers for Transdermal drug delivery system.

The polymer should be stable. non-reactive with the drug. easily manufactured and fabricated into the

desired product and inexpensive. The polymer and its degradation products must

be non-toxic or non-antagonistic to the host. The mechanical properties of the polymer should

not deteriorate excessively when large amounts of active agent are incorporated into it.

TYPES OF TRANSDERMAL PATCHES

SINGLE LAYER DRUG ADHESIVE MULTI LAYER DRUG ADHESIVE

MATRIX RESERVOIR PATCH

Quality control tests for topical preparations(TDDS)

Physicochemical evaluation In vitro evaluation In vivo evaluation

1. Physicochemical Evaluation Thickness: The thickness of transdermal film is determined by travelling microscope, dial gauge, screw gauge or micrometre at different points of the film.

Uniformity of weight: Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight.

Drug content determination: An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectro-photometrically by appropriate dilution Content uniformity test: 10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to 125% of the specified value, then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to

115%, then the transdermal patches pass the test.

Moisture content: The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula. % Moisture content = Initial weight – Final weight X 100

Moisture Uptake: Weighed films are kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below. % moisture uptake = Final weight – Initial weight X 100 Flatness: A transdermal patch should possess a smooth surface and should not constrict with time. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured

Folding endurance: A strip of specific are is to be cut evenly and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking gave the value of the folding endurance. Tensile Strength: One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. A pointer on the thread is used to measure the elongation of the film. The weight just sufficient to break the film is noted. Water Content: A test for water content should be included . Microbial Limits: The type of microbial test(s) and acceptance criteria should be based on the nature of the drug substance, method of manufacture etc. Sterility: Depending on the use of the dosage form, e.g., ophthalmic preparations, sterility of the product should be demonstrated as appropriate

Viscosity: Rheological properties such as viscosity of semisolid dosage forms can influence their drug delivery. Viscosity may directly influence the diffusion rate of drug at the microstructural level. Water vapour permeability (WVP) evaluation:It can be determined with foam dressing method the air forced oven is replaced by a natural air circulation oven. Polariscope examination: This test is to be performed to examine the drug crystals from patch by polariscope. A specific surface area of the piece is to be kept on the object slide and observe for the drugs crystals to distinguish whether the drug is present as crystalline form or amorphous form in the patch. Adhesive propertiesShear Adhesion test: This test is to be performed for the measurement of the cohesive strength of an adhesive polymer. It can be influenced by the molecular weight Tack properties: It is the ability of the polymer to adhere to substrate

Peel Adhesion test: In This test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180°C angle, and the force required for tape removed is measured

Rolling ball test:

2. a. In vitro release studies The Paddle over Disc: This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C. The Cylinder modified USP Basket: This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C. The reciprocating disc: In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug.

b. In vitro permeation studies The amount of drug available for absorption to the systemic pool is greatly dependent on drug release. Horizontal-type skin permeation system: This has been widely used for the evaluation of drug permeation across skin.

Franz diffusion cell: The cell is composed of two compartments: donor and receptor. The receptor compartment has a volume of 5-12ml. The diffusion buffer is continuously stirred at 600rpm by a magnetic bar. The temperature in the bulk of the solution is maintained by circulating thermostatic water through a water jacket that surrounds the receptor compartment.

Flow-through diffusion cell: Flow through diffusion cells have the advantage that they can be used when the drug has lower solubility in the receptor compartment. This cell can be fully automated and connected directly to HPLC.

3. In vivo Studies In vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out using animal models human volunteers. Animal models: The most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, rabbit, guinea pig etc. Rhesus monkey is one of the most reliable models for in vivo evaluation of transdermal drug delivery in man.

Skin Irritation study Skin irritation and sensitization testing can be performed on healthy rabbits (average weight 1.2 to 1.5 kg). The dorsal surface (50cm2) of the rabbit is to be cleaned and remove the hair from the clean dorsal surface by shaving and clean the surface by using rectified spirit and the representative formulations can be applied over the skin. The patch is to be removed after 24 hr. and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury. Stability studies Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyse suitably for the drug content.

Human models: The final stage of the development of a transdermal device involves collection of pharmacokinetic and pharmaco-dynamic data following application of the patch to human volunteers. Clinical trials have been conducted to assess the efficacy, risk involved, side effects, patient compliance etc. Phase I clinical trials are conducted to determine mainly safety in volunteers and phase II clinical trials determine short term safety and mainly effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population and phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions. Though human studies require considerable resources but they are the best to assess the performance of the drug.

REFERENCESTransdermal Drug Delivery

Technology http://www.pharmainfo.net.

Dispensing Pharmacy – RM MEHTA