PERFORMANCE CHARACTERISATION OF HPMC

CAPSULE: ANALYSIS OF PHYSICOMECHANICAL AND MANUFACTURING ASPECTS

Presented By: DHRUTI AVLANI

B.Pharm, 4th year, 7th semesterRegistration No.: 122770210011Roll No.: 27701912011NSHM Knowledge Campus, Kolkata – Group of Institutions

GUIDE: Dr.Sutapa Biswas Majee

INTRODUCTIONCapsules are solid dosage forms in which one or more medicinal and inert ingredients are enclosed in a small shell or container usually made of gelatin.

The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation of stomach.

TYPES :

1) Hard (two piece) Capsule 2)Soft (one piece) CapsuleADVANTAGES :

DISADVANTAGES :

Mask the taste and odour of unpleasant drugs. Attractive in appearance, easy administration, economical. Shells are physiologically inert and quickly digested in the gastrointestinal tract. Shells can be opacified (with titanium dioxide) or coloured, to give protection from light.

WHY GELATIN IS PREFERRED AS A CAPSULE SHELL MATERIAL?

Non - toxic

Soluble in hot water and sets to form a gel on cooling

Good film-forming material, producing a strong flexible film

The gelatin films are homogeneous in structure, which gives them

strength

Readily soluble in biological fluids at body temperature

NEED FOR AN ALTERNATIVE TO GELATIN

CROSS - LINKING• Causes -

• Excipients undergo auto oxidation.

• High temperature and humidity.

• Water soluble proteins, example lysine.

MOISTURE SENSITIVITY• Moisture

content <12%, hygroscopic formulation – gelatin film becomes brittle.

• Moisture content >18% - gelatin film becomes soft.

RELIGIOUS• Animal

source of gelatin can be a problem for certain consumers such as vegetarians, religious or ethnic groups.

OTHERS• Maillard

reaction –discolouration of the capsule.

• Special packaging and storage conditions to ensure product stability.

HPMC AS AN ALTERNATIVE HPMC stands for Hydroxypropyl Methyl Cellulose. Also known as Hypromellose. It is a methyl and hydroxypropyl mixed ether of cellulose. It is a natural polysaccharide found in all plant parts mainly wood.

PROPERTIES : White to slightly off white powder or granules . It is a semisynthetic, inert polymer. It is insoluble in hot water, acetone and chloroform. It is soluble in cold water giving a colloidal solution owing to the reversible thermal gelation property.

WHY HPMC?

GELATIN HPMC

Higher stability at different conditions

MANUFACTURING OF CAPSULES

Mixing Of Raw

Materials Dipping Drying

Coating/Banding And

PolishingCapsule Filling

Positioning And

Stripping

NO Stringent Gelation Conditions

PATENTED TECHNOLOGIES

QUALI-V®

Shionogi Qualicaps

Carrageenan Gelling Agent

Moisture Content: 4-6%

CAPSULE SHELL MATERIAL Inspite of gelatin being the most widely used capsule shell

material, it has various disadvantages (animal source, cross-linking property, moisture sensitive) and an alternative was required to overcome the problems. So, HPMC has been considered as a good alternative to gelatin.

The main area where HPMC capsules can have better prospect compared to gelatin capsules is in wider patients’ preferences since it is not derived from animal source (skin or bones). It does not show any cross linking property and is highly stable at different conditions.

The use of HPMC as an alternative to gelatin as capsule shell material can only be confirmed by analysing and comparing the quality control parameters of the empty and filled HPMC vs Hard Gelatin capsules. (literature data)

PHYSICOMECHANICAL PARAMETERS• Capsule

Dimensions• Scanning

Electron Microscopy

• Mechanical Strength

• Weight Variation• Transport

Simulation Test

IN-VITRO TESTS• Formaldehyde

Challenge Test• In-vitro

Disintegration & Dissolution Test

IN-VIVO TESTS• Oesophageal

Sticking Tendency

• In-vivo Disintegration & Dissolution Test

• Animal Data• Human

Bioavailability

INVITRO – INVIVO

CORRELATION AND STABILITY

STUDIES

CAPSULE SHELL EVALUATION

PHYSICOMECHANICAL EVALUATION

1) FORMALDEHYDE CHALLENGE TESTCapsules were filled with lactose spiked with formaldehyde at 25 ppm

Capsules were emptied and filled with acetaminophen at a fill weight 380 mg (±10 mg)

The capsules were tested as per the acetaminophen capsules USP monograph for Acetaminophen Capsules – Dissolution Test with water

and USP apparatus II (paddle, 50 rpm)

After 1 week storage at room temperature, dissolution of acetaminophen from the HPMC shell is unchanged while gelatin shell observed significant

dissolution slow down

1 week storage in HDPE bottles at room temperature

PERFORMANCE EVALUATION

Cross-linking susceptibility of capsules is assessed by comparing the dissolution results.

2) OESOPHAGEAL STICKING TENDENCY

HPMC is a bioadhesive

material

Therefore it is expected that an increase in the oesophageal

residence time would occur before reaching stomach.

Both HPMC and Gelatin capsules are administered

simultaneously with 180 ml water to eight healthy male

subjects following an overnight fast.

No prolonged oesophag-eal hold-ups,even for HPMC

capsules

To avoid oesophagus

entrapment of solid dosage

forms, they should be taken in upright body position with at least 50 mL of water to minimize

entrapment

INFERENCE

METHOD

PRINCIPLE

3) INVIVO DISINTEGRATION AND DISSOLUTION TEST

IN-VIVOSTUDIES

PRINCIPLE:Capsules

radiolabled with indium-

111, filled with a plug of

lactose-based formulation

and administered

simultaneously to each

individual with 180 ml of

water.

RESULT:HPMC Capsule

– 9 minsGelatin

Capsule – 7 mins

INFERENCE:Due to this

minimal difference,

HPMC is considered as an alternative

to Gelatin capsules.

PARAMETERS

ANIMAL DATA HUMAN DATA

SPECIES Dog (4 male dogs) Humans (6 human beings)CONDITIONS Overnight fast and fed state Overnight fast and fed

statePARAMETER Tmax TmaxPRINCIPLE METHOD

Blood samples were drawn up to 24 or 30 h after dosing; plasma was separated, analyzed for drug content and validated by mass spectroscopy.

Blood samples were collected up to 72 h post-dose, plasma separated and analyzed for drug content with a validated by mass spectroscopy.

RESULTS for immediate release formulations

• HPMC capsules reflected a rapid Tmax, indicating that the dissolution of the capsule shell was not rate-limiting for absorption.

• Short Tmax reflects rapid in vivo dissolution of HPMC capsules.

• The median Tmax of ~1h in fast state reflects the rapid disintegration of the HPMC capsule shell.

• Thus, HPMC capsules yield a quick in-vivo plasma profile for humans.

4) ANIMAL & HUMAN BIOAVAILABILITY

• HPMC: No change in dissolution of the compound from capsule shell

• GELATIN: Significant slow down in dissolution takes place

1) FORMALDEHYDECHALLENGE

TEST

• HPMC: Slow, but does not cause any delay in drug absorption

• GELATIN: Fast

2) IN-VITRODISINTEGRATION& DISSOLUTION

• No sticking tendency for both the capsule shells

• To avoid oesophagus entrapment of solid dosage forms, must be taken in upright body position with water to minimize entrapment

3) OESOPHAGEALSTICKING

TENDENCY

PERFORMANCE EVALUATION

• HPMC: 9 mins ; GELATIN: 7 mins• Due to this minimal difference, HPMC is

considered as an alternative to Gelatin capsules.

4) IN-VIVODISINTEGRATION& DISSOLUTION

• HPMC: Rapid Tmax indicates dissolution of the capsule shell was not rate-limiting for absorption whereas short Tmax reflects rapid in vivo dissolution of HPMC capsules.

5) ANIMALDATA

• HPMC: The median Tmax of ~1h in fast state reflects rapid disintegration of the HPMC capsule shell. Therefore they yield a quick invivo plasma profile for humans.

6) HUMANBIOAVAILABILITY

STABILITY STUDIES

VISUAL EVALUATION

HPMC SHELL : • No change

upto 40°C• Deformed at

70°CGELATIN SHELL:• No change

upto 50°C• Deformed at

60°C

DISINTEGRATIONDISSOLUTION

HPMC SHELL: • No change

upto 90°C

GELATIN SHELL: • No change

upto 60°C• Deformed at

60°C

MECHANICALSTRENGTH

HPMC SHELL: • No change

upto 90°C

GELATIN SHELL: • No change

upto 60°C• Deformed at

60°C

HPMC capsules (200 capsules) were filled into glass bottles and heated at different temperatures (up to 90 °C) for 24 h in an oven. The glass bottles are kept at room temperature for at least 5 h before opening and the capsules were evaluated on these parameters.

PARAMETERS HPMC CAPSULE GELATIN CAPSULEScanning Electron

Microscopy

Clean edge with a very smooth surface - no

leakage, better disintegration studies

Rough edge with a smooth surface- no

leakage

Mechanical Strength

At low humidity- maintain elasticity and resist breakage. [2-7% moisture content at 10-

60% RH]

At low humidity- become brittle and exhibit higher breakage rates. [13-16% moisture content at 35-

65% RH]Weight Variation Not significant, therefore low

rejection rateNot significant, therefore

low rejection rateTransport

Simulation TestNo leakage No leakage

CAPSULE SHELL EVALUATION1. PHYSICOMECHANICAL EVALUATION

PARAMETERS HPMC CAPSULE GELATIN CAPSULEFormaldehyde Challenge Test

No change in dissolution of the compound from capsule shell

Significant slow down in dissolution takes

placeIn-vitro & In-vivo Disintegration & Dissolution Test

Slow, but does not cause any delay in drug absorption

Dissolution Time: 9 minutes

FastDissolution Time: 7

minutesOesophageal

Sticking TendencyNo sticking tendency No sticking tendency

Animal Data Rapid Tmax indicates dissolution of the capsule shell was not rate-limiting

for absorption whereas short Tmax reflects rapid in vivo dissolution of

capsules.

-

Human Bioavailability

The median Tmax of ~1h in fast state reflects rapid disintegration of the HPMC capsule shell. Therefore they

yield a quick invivo plasma profile for humans.

-

Stability Studies Stable upto 90°C Stable upto 60°C

2. PERFORMANCE EVALUATION

HPMC capsule is superior to hard gelatin capsules in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. It exhibits better short term stability at high temperature conditions and remains flexible even at low moisture content.

Water in HPMC shell walls does not act as a plasticizer. Thus if they lose water when they are exposed to low humidities during storage or if the formulation filled in to them is hygroscopic then they do not become brittle.

Two important areas where improvements have to be achieved in order to qualify the HPMC capsules ahead of Gelatin capsules are in their machineability and in the in vitro and in vivo disintegration/dissolution performances.

CONCLUSION

FUTURE PROSPECTS

Oxygen penetration through shell walls is about 3 fold slower for Gelatin than HPMC capsule. to put this into perspective it must be remembered that the bulk of the oxygen will enter the capsule through the gap between the cap and the body.

Band-sealing of HPMC capsules can reduce the amount penetrating into the capsule. An anti-oxidant can also be included in the formulation.

Pullulan is a natural water-soluble high molecular polysaccharide produced from starch. It exhibits low oxygen transmission and extended shelf life. Eg: NPcaps

REFERENCES1) Khar Roop K., Vyas SP, Ahmad Farhan J., Jain Gaurav K. (Eds),

Capsules in Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, 4th Edition, CBS Publishers & Distributors Pvt. Ltd., New Delhi, 546 – 578.

2) Moawia M. Al-Tabakha, HPMC Capsules: Current status and future prospects, J Pharm Pharmaceut Sci, 2010, 13, 428 – 442.

3) Rabadiya Bhavisha, Rabadiya Paresh, A Review: Capsule shell material from gelatin to non animal origin material, International Journal Of Pharmaceutical Research And Bio-Science, 2013, 2, 42-71.

4) Stegemann Sven, Hard Gelatin Capsules today – and tomorrow, Capsugel, 2nd edition, 2002, 1-23, http://www.capsugel.com (accessed as on July 7, 2015)

THANK YOU!