The document discusses the formulation and manufacturing processes of topical pharmaceuticals, focusing on components such as vehicles, emollients, and absorption factors affecting drug delivery through the skin. It details various raw materials used in medicated semisolid formulations, their functions, and types, alongside preservation methods and the requirements for microbiological testing. Additionally, it outlines specific manufacturing methods, especially the fusion method for semisolids, and emphasizes the importance of adhering to USP standards for quality and safety.

1. 1
Presented by:
Asst. Prof. MA. LOURDES LICSI-MOJARES,
RPh
CEU School of Pharmacy

2. USES OF TOPICAL
PHARMACEUTICALS
 VEHICLES FOR TOPICALLY –
APPLIED DRUGS
( Non-medicated ointment bases)
 EMOLLIENTS – provide soothing /
softening effects on the surface
tissues
 PROTECTIVES / OCCLUSIVE
DRESSINGS
2

3. FACTORS INFLUENCING
ABSORPTION
OF DRUGS THROUGH THE SKIN
A. Partition Coefficient of Drugs through the
Skin
Substances possessing both water
and lipid solubility are favorably
absorbed through the skin.
3

4. FACTORS INFLUENCING ABSORPTION
OF DRUGS THROUGH THE SKIN
B. Moisture and Temperature in the Environment
of the Skin
B.1 Moisture Balance in the Skin
It is found in the stratum corneum layer of the
epidermis.
It prevents the NMF (Natural Moisturizing
Factor) from being stripped from the skin.
NMF prevents skin from drying out, even
during excessive contact of the skin with water.
4

5. FACTORS INFLUENCING
ABSORPTION
OF DRUGS THROUGH THE SKIN
B.2 Insensible Perspiration
The skin constantly releases water in the
skin surface, which evaporates quickly
without being noticed.
When the surrounding environment has
a high moisture content, the rate of
evaporation of sweat is slowed down,
and the person becomes aware of the
clammy moist sensation on his skin.
5

6. FACTORS INFLUENCING ABSORPTION
OF DRUGS THROUGH THE SKIN
C. Pathological Injury to the Skin
Skin penetration has been enhanced
by abrasions or when the skin is
stripped of its barrier layer.
6

7. FACTORS INFLUENCING ABSORPTION
OF DRUGS THROUGH THE SKIN
D. Type of Vehicle Used
Skin penetration of drug substances
may be enhanced by the use of a
suitable semisolid base.
The vehicle may help increase the rate
of penetration of a drug substances
into the skin.
It serves as a carrier for the API.
7

8. RAW MATERIALS IN THE FORMULATION
OF
MEDICATED APPLICATIONS
FDA approves chemical substances and
states the maximum concentration
considered safe for food and cosmetics
(GRAS grade).
The supplier of these drug substances
supplies brochures / information which
indicates that FDA APPROVAL SAFETY
TESTS are conducted.
8

9. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 HYDROCARBONS
Petrolatum and Mineral oil are the MOST
WIDELY USED substances in semisolids,
next to water.
PETROLATUM– a complex mixture of
semisolids containing hydrocarbon aliphatic,
cyclic, saturated, unsaturated, branched and
unbranched substances in varying
proportions.
MINERAL OIL – derived from petroleum acid.
It is less tacky and with lower viscosity.
9

10. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 HYDROCARBON WAXES
1. Help increase the viscosity of
hydrocarbons such as petrolatum and
mineral oil
2. prevent separation of hydrocarbons
from the ointment.
Examples: paraffin, beeswax, ceresin wax
(mixture of paraffin and
ozokerite).
10

11. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 OLEAGINOUS SUBSTANCES
Vegetable fixed oils which contain
glycerides of mixtures of saturated and
unsaturated fatty acids (MCT’s and FA’s).
These are employed for its EMOLLIENT
and SKIN-LUBRICATING effects.
Examples: Fixed oils of peanut, olive,
sesame, cottonseed, coconut, corn
11

12. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 FATTY ACIDS and ALCOHOLS
Functions as;
1. auxiliary emulsifiers
2. viscosity –builders
Examples:
Stearic acid – emulsifiers in water-removable
creams
Stearyl / Cetyl Alcohols - emollients, provides
the necessary firmness / softness in consistency
of creams.
12

13. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 EMULSIFIERS
Substances that;
a. Prevent Coalescence
b. act as Product stabilizers
Examples: Triethanolamine stearate,
SPANS, TWEENS, Carbowax
13

14. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 POLYOLS
Used as Humectants, prevents
dehydration and “Crusting” on top of
creams and ointments in jars.
Examples: Glycerin, PG, Sorbitol 70%,
PEG (lower MW)
14

15. THE FREQUENT RAW MATERIALS FOR
MEDICATED SEMISOLIDS
 INSOLUBLE POWDERS
These must be uniformly dispersed
throughout the semisolid vehicle to
assure product homogeneity.
These solids must be impalpable to the
touch..
Particles less than 74 micronsParticles less than 74 microns
(equivalent to 200 mesh) is said to be(equivalent to 200 mesh) is said to be
impalpable to most peopleimpalpable to most people..
15

16. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 Factors which Influence the Choice of
Semisolid Vehicles
1. Nature of the skin lesion
2. Skin Type
3. Solubility of the formulation
components
4. Stability of the API’s
16

17. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 HYDROCARBON BASES
 Typically lipophilic
 Spreads easily onto the skin
 Difficult to remove / wash-off
 Act as occlusive dressings, since the
normal evaporation of insensible
perspiration is inhibited.
 Examples are White petrolatum, Mineral
oil, White / Yellow Ointment, USP
17

18. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 ABSORPTION / EMULSIFIABLE BASES
 These are hydrophilic mixtures formed by
the addition of substances that possess
polar groupings ( sulfates, carboxyl, hydroxyl
or ether linkages) to a Hydrocarbon Base.
Lanolin, Cholesterol, Sorbitan
monostearate / monooleate are added to
Hydrocarbon bases to make it hydrophilic.
18

19. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 WATER – REMOVABLE / WASHABLE
BASES
 These are o/w emulsions referred to as
Creams.
 Upon application, there is little or no
evidence of its presence onto the skin.
 Best for moist skin lesions, since its o/w
character tend to adsorb serous
discharges.
19

20. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 WATER – REMOVABLE / WASHABLE
BASES
 Vanishing creams, Foundation
creams, Shaving Creams.
 Vanishing creams type of vehicles
are of o/w type.
 Absorption bases are of w/o type.
20

21. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 WATER-SOLUBLE / GREASELESS
BASES
 Prepared from mixtures of high and
low MW PEG
 No water is required in its
preparation
 Water soluble, due to many polar
groups and ether linkages
21

22. TYPES OF SEMISOLID VEHICLES
NON-MEDICATED BASES
 WATER-SOLUBLE / GREASELESS BASES
 Suitable combinations of high and low
MW PEG yield products having an
ointment-like consistency, which soften or
melt when applied topically.
 Low MW PEG – liquids
 Moderately high MW PEG – unctuous
 Very High MW PEG - solids
22

23. OPTHALMIC OINTMENTS
 Semisolid ophthalmic vehicles frequently
contain any of the ff. bases that have been
sterilized;
1. petroleum jelly
2. absorption base
(Lanolin or Lanolin Alcohol)
3. water-soluble base
 Insoluble API powders should meet the
requirements for IMPALPABILITY.
 Ophthalmic ointments should be rendered
STERILE and ISOTONIC.
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24. OTHER
OPTHALMIC OINMENT BASES
 Lanolin
Sterilized by Gamma Radiation or
Sterilization by Filtration
 Lanolin Alcohol
Possess emollient properties suitable
for eye ointment formulation.
24

25. 25

26. PRESERVATION FROM MICROBIAL
SPOILAGE
 The chemical preservative for
semisolids should be evaluated as to:
1. Stability with regard to formulation
components
2. Container to be used.
26

27. CHARACTERISTICS OF
PRESERVATIVES
FOR SEMISOLID PRODUCTS
 Some preservatives become inactive
in the presence of other ingredients.
 Boric acid may be used in ophthalmic
ointments against bacterial/ fungal
contamination.
 Bacterial counts should be made on
the water supply, RM, pipelines, filling
equipment and containers.
27

28. USE OF ANTI-OXIDANTS
 Anti-oxidants are added to semisolids,
whenever oxidative deterioration is
anticipated.
 BHA, BHT, Propyl gallate
28

29. USE OF ANTI-OXIDANTS
 The choice of anti-oxidant is made
upon consideration of the following
factors:
1. toxicity / irritating potency
2. compatibility
3. odor
4. discoloration
5. solubility
6. stability
29

30. MANUFACTURING PROCESS OF
SEMI-SOLIDS
 Factors to be controlled during the
Fusion Method:
1. Time of mixing
2. Temperature of mixing
3. Rate of agitation ( and other mechanical
works)
30

31. MANUFACTURING PROCESS OF
SEMI-SOLIDS
 FUSION METHOD
ANHYDROUS OINTMENTS are
manufactured by this process, which is
made by dissolving the API’s in the
previously melted fats and waxes.
The melted mass must be mixed while
cooling to ensure the homogenous
distribution of the ingredients.
31

32. STEPS IN FUSION METHOD
Step 1: PREPARATION OF THE OIL PHASE
Flake / pulverize the dry ingredients.
Heating is required to melt some
ingredients (waxes), usually at 700
C to
750
C.
Blend in advance and disperse in mineral
oil or silicone oil.
32

33. STEPS IN FUSION METHOD
Step 2: HYDRATION OF THE INGREDIENTS
IN THE AQUEOUS PHASE
Emulsifiers, stabilizers, thickening agents
are dispersed into water in a separate
vessel.
Usually followed by a filtration procedure,
if needed.
Heating may be required to accelerate
hydration.
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34. STEPS IN FUSION METHOD
Step 3: FOAMING THE EMULSION
The aqueous and oil phases are blended
under vigorous agitation, to form the
emulsion.
Temperature is controlled between 300
C to
400
C.
Defoaming procedures are done to minimize
foam formation after the product has
emulsified.
34

35. STEPS IN FUSION METHOD
Step 4: DISPERSION OF THE ACTIVE/S
The API’s make up only a small
proportion of the formulation.
It must be EFFICIENTLY DISPERSED to
maximize yield and product
effectiveness.
35

36. PROCESS FLOW DIAGRAM of
TOPICAL PHARMACEUTICALS
MANUFACTURE
36

37. PLASTIC TUBE
FILLING and SEALING MACHINE
37

38. METHODS OF FILLING
OPTHALMIC OINTMENTS
 BLOW FILL SEAL METHOD (BFS)
SEQUENCE in ONE EASY
OPERATION:
1. Fabrication of containers
2. Filling the product
3. Sealing
38

39. METHODS OF FILLING
OPTHALMIC OINTMENTS
 FORM FILL SEAL METHOD (FFS)
The conventional method of filling
opthalmic ointments.
39

40. STRAIGHT-
SIDED
GLASS and PET
JARS for
CREAMS
and
OINTMENTS
40

41. FILLING MACHINE OINTMENT
FOR OINTMENTS PRODUCTION
41

42. COLLAPSIBLE TUBE
FILLING AND SEALING MACHINE
 Makes use of the
“Hot Melt” Sealing
system.
 Fills and Seals 85
collapsible tubes
per minute.
42

43. Specialty
packaging for
ointments
intended for;
 Nasal
 Rectal
 Vaginal
 Opthalmic
43

44.  STORAGE and LABELING
 MICROBIAL SCREENING
( Microbial Limit Tests)
1. Staphylococcus aureus
2. Pseudomonas aeruginosa
44
As per USP Requirements:

45.  MINIMUM FILL
Assessment of the Content Uniformity of
semi-solids.
Product weighing 60 g or mL – nlt 90% of
the labeled amount.
Product weighing 60 g or mL to 150 g or
mL – nlt 95% of the labeled amount.
45
As per USP Requirements:

46.  STANDARD ASSAYS of the API’s
(Quantitative assay of % Purity or %
Content)
 STERILITY TESTS
1. Membrane Filtration Technique
2. Test Tube Inoculation Method
46
As per USP Requirements:

47.  In vivo BA/BE – Dermatopharmacokinetic
Studies (DPS)
Applicable to semisolids that contain:
1. Antifungals
2. Antivirals
3. Corticosteroids
4. Antibiotics
5. Topicals for vaginal use
47
As per USP Requirements:

48.  In vivo BA/BE – Dermatopharmacokinetic
Studies (DPS)
Not applicable to semisolids for;
a. otic use
b. opthalmic use
c. that damage the stratum corneum of the
skin.
48
As per USP Requirements:

49.  In vivo BA/BE – Dermatopharmacokinetic
Studies (DPS)
It involves measurement of the ff.;
1. drug concentration in the stratum
corneum
2. drug uptake
3. apparent steady state
4. elimination after drug application onto
the skin
49
As per USP Requirements:

50. As per Non- USP requirements
 pH
 Water Content (Karl Fisher
Method)
Water affects the;
a. physical stability
b. chemical stability
c. microbial stability
50

51. Usual water limit: 0.5% to 1%
NMT 0.5% water content for
Ointments containing:
1. Bacitracin
2. Chlortetracycline HCl
3. Nystatin
51

52. NMT 1% water content for
ointments, creams or gels
containing;
1. Erythromycin
2. Gentamycin sulfate
3. Neomycin sulfate
4. Tetracycline HCl
52

53.  Foreign Substances
 Homogeneity
( also refers to Content
Uniformity by Minimum Fill
testing)
53

54.  Metal Particle Detection Test –
mandatory for opthalmic ointments
only.
Limits:
NMT 3 tubes out of the 10 tubes
tested should contain 8 metal
particles.
54

55.  Leaker Test
Mandatory for opthalmic ointments
filled in collapsible tubes.
By Classical Blotting Paper Method
55

56. Specs / Limits:
NMT 1 tube out of the 10 tubes should
leak.
If MT 1 tube leaks, repeat the test on
20 additional tubes.
NMT 1 tube out of the 30 tubes should
leak.
56