CAPSULES

PhD. NGUYEN PHUOC VINH

1
 Definition
Solid dosage form with APIs
encapsulated within a capsule.
Capsules are made of gelatin, starch
or cellulose derivatives

Application: P.O or as suppository

Classification: Hard vs Soft

capsules

2
 Advantages

•Ready for P.O

•Taste masking
•Protection against light and humidity
•Better bioavailability than tablets

For new APIs Precise dose for liquid drugs

3
 Disadvantages

Lower stability than tablets Not suitable for conventional

(humidity, heat) hydrophillic APIs

Stability for herbal extracts

4
 Gelatin
Gelatin (18 acid amin)

- Use in food and drug, safety

- Soluble in physiological fluids

- Able to form film at 100μm

- Concentrated solution of 40% is melted at 50 oC

- Phase transition (solution🡪 gel) within a narrow change in

temperature and close to ambient temperature

5
 Gelatin
Gelatin (18 acid amin)
Acid
Episkin Gelatin A
(pHi = 4,8 – 5)
7 – 10 days

Acid
Colloidal
Cow bones (elimination of calcium phosphate)

Alkaline
Weeks
Gelatin B
(pHi = 7 - 9)
6
 Gelatin
Quality requirements

Gel stability (Bloom number)

Cylinder, d = 0,5 inches

Hard capsule
150 – 280 Bloom gram
4mm
Soft capsule
100 – 200 Bloom gram

Solution gelatin 6,66% (w/v)

10 oC
16 – 18 hours
7
 Gelatin
Quality requirement

Viscosity

Hard capsules: solution of gelatin 2 – 6% (w/w)

60°C
30-60 mps

Soft capsules: solution of gelatin 6,66% (w/v)

60°C
25 – 45 milipoise

8
 Gelatin
Quality requirements

Iron concentration
nmt 15ppm

Microbial limits
nmt 1000 microrganism in
1 g of gelatin without any
Samonella or E. coli

9
 Hard capsules

Body

Capsul
Intermedicate
e position

Body + cap after drug filling

10
 Hard capsules

Hard capsules: body + cap, 08 sizes,

volum varies 0,13 – 1,36ml.

Size 000 00 0 1 2

Volu 1,36 0,95 0,67 0,48 0,38

me
(ml)
11
 Fabrication of hard capsules
Fabrication of hard capsules
Composition of hard capsules
1. Gelatin
2. Coloring agent: soluble dye, pigment
3. Opacifying agent: titanium dioxide
4. Preservatives: paraben, sulfur dioxide (sodium
metasulfite or sodium sulfite)
5. Water: RO water, 12-16% water.
6. Sodium lauryl sulphate: under 0,15% w/w.
12
 Fabrication of hard capsules

Solution of 30-40% gelatin +

excipients

Molding (50 oC, 12 s)

Rounding at horizonal direction

(avoid of droplet formation)

Drying (use of dry and cold air with

appropriate speed)

Removing, cutting, put cap and body

together
13
Hard capsules
Hard capsules

15
 Drug filling into hard capsules
Drug filling
Determination of specific gravity of granules
Weight = Specific gravity x Volume

Determination of capsule size

Determination of filler amount

Mixing + Drug filling

16
 Drug filling method
Drug filling
Encorafenib 50mg
PVP K30 17mg
Poloxamer 188 5mg
Avicel pH 101 10mg
Succinic acid 5mg
Crosspovidone 3mg
Silica colloidal anhydrous 0,1% cốm
Magnesium stearate 0,25% cốm

Specific gravity of granules 0,78 g/mL, that of

pulverized lactose 0,8 g/mL. Choose the
size? Calculate the amount of Lactose?
17
Drug filling method

Volume of granules for

20 units is 12 mL,
determine the size of
appropriate hard
capsules and calculate
the necessary amount
of lactose for the
complete mixing (given
the specific gravity of
lactose is 0,8 g/mL)

18
 Drug filling into hard capsules

Determine of specific gravity of granules

Weight = specific gravity x capsule size

Determination of capsule size Lubricants: magnesium

stearate, calcium stearate,
aerosile (colloidal silicone
dioxide) … 0.5-1%
Determination of filler, lubricant added Filler: starch, lactose….

Wetting agent: Sodium lauryl

sulfate
Complete mixing

19
 Drug filling methods
Drug filling according to volume

Speed: 15 000 – 25 000 units/hour

20
 Drug filling methods
Automatic filler
Đóng nang bằng vít phân liều (DĐóng
nang bằng vít phân liều (Dosator)
Speed: 5 000 – 150 000 Units/Hours

21
 Kỹ thuật điều chế nang cứng
Automatic filler
Đóng nang bằng vít phân liều (Dosator)

Speed: 5 000 – 150 000 units/hours

- Good compressibility
- Good flowability
- Anti-adhesion property
- Intermediate specific gravity is recommended

22
 Bioavailability of hard capsules

Disintegration

•The bigger the size is, the longer the

disintegration time is

•The lower pH is, the better the capsule is

disintegrated
•Interaction between capsules and API (aspirin)
•Degradation of capsules
•Anti-falsificating and anti-hygroscopic capsules

23
 Bioavailability of hard capsules

Wetting and diffusion process

APIs properties
Porosity and capillary system within the granules
Excipients

Water

Water 24
 Bioavailability

Wetting and diffusion process

Size of sulfisoxazole Chlordiazepoxide / Magnesium stearate

25
 Sinh khả dụng viên nang cứng

Wetting and diffusion process

Rifampicin/ Magnesium stearate Hydrochlorthiazide/ Magnesium stearate

26
 Classification

Soft capsules: Soft, elastic gelatin capsule (SEG)

1 ml = 16,23 minim
Oral soft capsules
Chewable capsules
Lozenges soft capsules
Viên vặn (twist-off)
Suppositories

27
 Fabrication of soft capsules
Composition of soft capsules:
Gelatin (B): 100 - 200 Bloom gam, 25 – 45 milipoise.
For hydrophyllic drug: low viscocity (25 – 32 milipoise)
+ High Bloom strength (180 – 200 Bloom gam) is
recommended.
Not more than 45% w/w of wet formulation (ratio of water
to dry gelatin vary 0.7 to 1.3 (water) to 1.0 (dry gelatin))

28
 Fabrication of soft capsules
Composition of soft capsules:
Gelatin (B)
Chất tạo độ dẻo (Plasticifiers): (glycerine, sorbitol,
propylene glycol) 20-30% w/w in wet formulation

Hom et al., 1975

29
 Fabrication of soft capsules
Composition of soft capsules:
Gelatin (B)
Plasticifiers
Water: 30-40% w/w in solution, 5-8% w/w in final weight.
Coloring agent: for 14-29 minims capsules
Opacifying agent
Stabilizers
Flavoring or aroma agents

30
 Fabrication of soft capsules
Composition of drugs:
Solution:
Hydrophobic drugs (vegetable oils, fish oils, mineral
oils, trigycerides derivatives): hydroxycholecalciferol,
vitamin D, oestradiol, vitamine A
Hydrophillic drugs (with high molecular weight),
glycerin, propylen glycol, ethanol, water, volatile solvents.
Suspension:
Wetting agent, emulsifying such as lecithine, soybean
oil, yellow wax, non-ionic surfactant (polyoxyethylen
sorbitan monooleate)

Particle size < 100 μm 31

 Fabrication of soft capsules
Composition of fill materials:
Chất tạo độ nhớt (Viscosity-enhancers)

32
 Fabrication of soft capsules
Composition of fill materials:
pH adjusters
2,5 - 7,5
Organic acids: citric, lactic, tartric
Alkaline agents: Sodium ascorbate, sodium acetate

33
 Fabrication of soft capsules
Composition of fill materials:
Volume
9 minims: Spherical shape
16 – 20 minims: Oval shape
> 20 minims: Cylinder shape
Viscosity
0,22 to 3000 cps.

34
 Calculation of capsule size

Base absorption value (BAV): number of grams of liquid base

required to produce the capsulated mixture when mixed with 1 gm of solid.
BA of solid is influenced by particle size, shape, physical state (fibrous,
amorrphous), its density, its moisture content, its oleophilic or hydrophilic
nature. In determination of a BA factor, the solid must be wetted completely
by the liquid base and a wetting agent is added if necessary

Minim / Gram factor (MG): is the volume in minims that is

occupied by one gram of solid plus the weight of the liquid base required to
make the capsulated mixture: M/G = {(BA + S) x V} / W

S = gram of solid

W = weight of the mixture

V = minim

35
Calculation of capsule size

36
Calculation of capsule size

37
 Calculation of capsule size
Fill materials:
30 gram of niacinamide needs 18,0 grams veg. Oils will
form a mixture with good flowability
BAV = 18,0/30 = 0,6
Specific gravity of solf capsule is 1,28 g/mL
Therefore, MG factor is:
(1 + BAV)/D = (1 + 0,6)/1,28 = 1,25 mL

38
 Calculation of capsule size
Fill materials:
40 grams APIs X needs 25 grams liquid oils to form a good
flowable mixture. The specific gravity of the mixture is
1,11 g/ml.
Calculate: BAV ??; M/G factor??; and Volume of soft
capsule (mL? minim?) for the formulation contaning 1
gram of API

39
 Fabrication of soft capsules
Phương pháp nhúng khuôn (molding methods)

Manual
Used for lab-scale

45-50 oC

Phương pháp ép khuôn (Plate,

Rotary die, Reciprotating die,
Accogel process)
Loss of material: 15 – 20%

Drug weight variety in capsules: 20 - 40%.

40
 Fabrication processes
Molding method

68-70°C Specific Gravity: 0,9-1,2 g/ml

Viscosity: 1-130cps
20-750mg
0,8-12,0 mm
8000-13000 Units/hours

Cold Paraffin, 4°C, 6-8 hours.

41
 Fabrication processes
Automatic process

68-70°C

0,6-1,2mm

38-40°C

IR drying
Isothermal and iso-humidity
drying (20-30% at 21-24°C)
13-14°C 42
 Fabrication processes
Automatic process

43
 VP5 for quality test

Identification and assay

Weigh Uniformity

Content uniformity

Disintegration time (30 phút)

Dissoulition rate (According to monograph) 44