1
FORMULATION OF SEMISOLID DOSAGE FORMS
2
INGREDIENTS USED FOR FORMULATING SEMISOLIDS INCLUDE
API, Bases, Antimicrobial preservative, Chelating agents, Humectants, Fragrances.
3
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
4
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.
5
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.
6
ANTIOXIDANTS: -Example of commonly used
antioxidants includeButylated hydroxy anisole (BHA, E320), Butylated hydroxy toluene.
7
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
8
HUMECTANTS: -Example of commonly used
humectants includes Poly Ethylene Glycol, Glycerol or Sorbitol
9
FRAGRANCES:-Examples of widely use fragrances are Lavender oil, Rose oil, Lemon oil, Almond oil
10
METHODS OF MANUFACTURING AND QUALITY CONTROL OF SEMISOLIDS
11
There are four methods of preparation,
BY TRITURAT
ION
BY FUSION
BY CHEMICA
L REACTIO
NS
BY OINTMENT
MILLS
12
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.
13
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.
14
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.
15
BY OINTMENT MILLS
It is used for large scale production where
triple roller mill is utilized which is faster than
others.
16
Quality assurance
and Quality control of
semisolids
Raw material
specification
In process control
Finished product
specifications
17
18
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
19
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
20
IN PROCESS CONTROL
Complete solubilization (if applicable)
pH Viscosity measurement Uniformity of distribution of active
ingredients Physical stability Measurement of density or specific
gravity.
21
MICROBIAL TEST
PHYSICAL TESTS
CHEMICAL TESTS
IN-VITRO RELEASE PROFILE TEST
INSTRUMENTAL ANALYSIS
FINISHED PRODUCT SPECIFICATIONS
22
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.
23
PHYSICAL TESTS
24
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
25
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.
26
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.
27
GELSControlled release gels OrganogelsExtended release gelsAmphiphilic gelsHydrophilic gelsNon aqueous gelsBioadhesive GelsThermosensitive sol-gel reversible
hydrogelsComplexation gels
28
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.
29
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.
30
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.
31
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.
32
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.
33
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.
34
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.