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FORMULATION OF SEMISOLID DOSAGE FORMS

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INGREDIENTS USED FOR FORMULATING SEMISOLIDS INCLUDE

API, Bases, Antimicrobial preservative, Chelating agents, Humectants, Fragrances.

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ACTIVE PHARMACEUTICAL INGREDIENTS

Disease treated API

Keratolytic Salicylic acid

Acne Sulphur, Resorcinol

Antipruritic Benzocaine, Menthol, Camphor

Emollient Lanolin

Anti-inflammatory Corticosteroid

Antifungal Benzoic acid, Salicylic acid

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BASES Ointment bases may be classified in several ways

but the following classification based on composition is generally used which are as follow,

A) Oleaginous bases. B) Absorption bases. C) Emulsion bases. D) Water soluble bases. E) Water removable bases.

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ANTIMICROBIAL PRESERVATIVES Some base, although, resist microbial attack but

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

Commonly used preservatives include

Methyl hydroxyl benzoate, Propyl- hydroxy benzoate, Chlorocresol, Benzoic acid, Phenyl mercuric nitrate, Benzalkonium chloride,Chlorhexidine acetate, Benzyl alcohol.

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ANTIOXIDANTS: -Example of commonly used

antioxidants includeButylated hydroxy anisole (BHA, E320), Butylated hydroxy toluene.

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CHELATING AGENTS: -chemicals that form soluble, complex

molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions to produce precipitates or scale

Example of commonly used chelating agents include Citric acid, Maleic acid

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HUMECTANTS: -Example of commonly used

humectants includes Poly Ethylene Glycol, Glycerol or Sorbitol

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FRAGRANCES:-Examples of widely use fragrances are Lavender oil, Rose oil, Lemon oil, Almond oil

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METHODS OF MANUFACTURING AND QUALITY CONTROL OF SEMISOLIDS

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There are four methods of preparation,

BY TRITURAT

ION

BY FUSION

BY CHEMICA

L REACTIO

NS

BY OINTMENT

MILLS

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BY TRITURATION

When base contain soft fats and oils or medicament is insoluble solid or liquid, then this method is use.

Application of shear forces. It is laboratory and small scale method

mostly using Mortar and Pastel.

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BY FUSION

When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring.

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BY CHEMICAL REACTIONS

In chemical method a new product is formed

by chemical reaction, which involves both

fusion and mechanical mixing.

Best example of such method is Iodine

ointment.

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BY OINTMENT MILLS

It is used for large scale production where

triple roller mill is utilized which is faster than

others.

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Quality assurance

and Quality control of

semisolids 

Raw material

specification

In process control

Finished product

specifications

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1. Description

2. Solubility

3. Identity

a. Specific chemical test

b. Infrared absorption

c. Ultraviolet absorption

d. Melting range

e. Congealing point

f. Boiling point or range

g. Thin layer, paper, liquid or gas

chromatoghraphy 4. Purity and quality

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a. General completeness of solutions, pH, specific rotation, non-volatile residue, ash, acid- insoluble ash, residue on ignition, loss on drying, water content, heavy metals, arsenic, lead, mercury, selenium, sulphate, chloride, carbonates, acid value , iodine value, saponification value

b. Specific quality tests ,particle size, Crystallinity characteristics ,and polymorphic forms

c. Specific purity tests , related degenerated products

5. Assay , calculated either on anhydrous or hydrous basis

6. Microbial limit test, especially for raw materials from natural sources

 

E. Test procedure

 

1. Compendial USP or NF references

2. Noncompendial, detailed analytical procedures, weights, dilutions, extraction, normality, reagent, instrumentation used and procedure, if any calculation

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IN PROCESS CONTROL

Complete solubilization (if applicable)

pH Viscosity measurement Uniformity of distribution of active

ingredients Physical stability Measurement of density or specific

gravity.

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MICROBIAL TEST

PHYSICAL TESTS 

CHEMICAL TESTS

IN-VITRO RELEASE PROFILE TEST

INSTRUMENTAL ANALYSIS

FINISHED PRODUCT SPECIFICATIONS

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MICROBIAL TEST Topical preparations are not require being

sterile. They must meet acceptable standards for

microbial contents USP chapter titled “Microbial Attributes of

Non sterile Pharmaceutical Products”. Betamethasone valerate ointment USP,

must meet the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa.

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PHYSICAL TESTS 

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CHEMICAL TESTS

Chemical tests to be performed includes Chemical potency test:-

Can be performed by using Animal Models.Content uniformity test:-

AssaypH measurement

Ph-Meter

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IN-VITRO RELEASE PROFILE TEST

Skin penetration involves use of some variety of a

diffusion cell like

Franz cell and

Flow through cell in which animal or human skin is

fastened to a holder and the passage of compounds

from the epidermal surface to a fluid bath is measured.

Hairless rats were sacrificed

The skin from the dorsal surface was excised, and the

adherent fat and subcutaneous tissue were removed.

The skin was mounted on Franz diffusion cells with the

epidermis facing the donor compartment.

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For the skin retention studies, the donor cell was removed, and the excess formulation was removed from the surface of the skin using a cotton swab.

The skin was then washed with 50% ethanol: water and blotted dry with lint-free absorbent wipes.

The entire dosing area (0.636 cm2) was collected with a biopsy punch.

Active drug content of epidermis and dermis was extracted using a previously reported method.

Briefly, the samples were homogenized and boiled for 10 minutes in solvent.

The samples were then centrifuged and the supernatant was collected for analysis of drug by HPLC.

The experiments were repeated at least 3 times using the skins from different rats.

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GELSControlled release gels OrganogelsExtended release gelsAmphiphilic gelsHydrophilic gelsNon aqueous gelsBioadhesive GelsThermosensitive sol-gel reversible

hydrogelsComplexation gels

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CONTROLLED RELEASE GELS  Drug delivery to nasal or ocular mucosa for either local or

systemic action suffers from many obstacles.

Gel formulations with suitable rheological and

mucoadhesive properties increase the contact time at the

site of absorption.

However, drug release from the gel must be sustained if

benefits are to be gained from the prolonged contact

time.

Case Study:- Gelrite gels were formed in simulated tear

fluid at concentrations of polymer as low as 0.1%, and it

was shown that sodium was the most important gel-

promoting ion in vivo.

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Kinetics:-

It was possible to control the release of uncharged drug

substances by including surfactants that form micelles

in the gel.

The release depends on lipophillic interactions between

the drug and the polymer and/or the micelles.

Controlled-release formulations of charged drugs could be

designed by mixing the drugs with oppositely charged

surfactants in certain fixed ratios.

In this way, vesicles in which the drug and surfactant

constituted the bilayer formed spontaneously.

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ORGANOGELS

Sorbitan monostearate, a hydrophobic nonionic

surfactant, gels a number of organic solvents

such as hexadecane, isopropyl myristate, and a

range of vegetable oils.

Gelation is achieved by dissolving/dispersing the

organogelator in hot solvent to produce an

organic solution/dispersion, which, on cooling

sets to the gel state.

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Cooling the solution/dispersion causes a

decrease in the solvent-gelator affinities, such

that at the gelation temperature, the surfactant

molecules self-assemble into toroidal inverse

vesicles.

Further cooling results in the conversion of the

toroids into rod-shaped tubules. Once formed,

the tubules associate with others, and a three-

dimensional network is formed which

immobilizes the solvent. An organogel is thus

formed.

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Sorbitan monostearate gels are opaque,

thermoreversible semisolids, and they are stable at

room temperature for weeks.

Such organogels are affected by the presence of

additives such as the hydrophilic surfactant,

polysorbate 20, which improves gel stability and alters

the gel microstructure from a network of individual

tubules to star-shaped "clusters" of tubules in the liquid

continuous phase.

Another solid monoester in the sorbitan ester family,

sorbitan monopalmitate, also gels organic solvents to

give opaque, thermoreversible semisolids.

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EXTENDED RELEASE GELS TIMERx is a controlled release technology consists of an

agglomerated, hydrophilic complex that, when

compressed, forms a controlled-release matrix. The

matrix, consisting of xanthan and locust bean gums

(two polysaccharides) combined with dextrose,

surrounds a drug core.

In the presence of water, interactions between the

matrix components form a tight gel while the inner core

remains unwetted.

The drug is encapsulated in the pores of the gel, and as

the matrix travels through the patient’s digestive

system, the tablet swells and begins to erode.

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This erosion allows the drug to “back-diffuse” out

through the gel-matrix at a controlled rate until the

matrix erodes and a majority of the drug is released.

The fundamental component controlling the rate of

release lies in the properties of the gel matrix.

Advantage of this system includes,

a) Predictable modified release profile like zero order or

first order or initial immediate release kinetics

b) It can be manufacture on standard manufacturing

equipment.

c) Cheap.