Transcript Document

Technology of Making Tablets
Murat Kizaibek
•
Tablets are solid dosage
forms consisting of active
ingredient(s) and suitable
pharmaceutical excipients.
They may vary in size,
shape, weight, hardness,
thickness, disintegration
and dissolution
characteristics, and in other
aspects. They may be
classyfied, according to the
method of manufacture, as
compressed tablets or
molded tablets.
Advantages
• Production aspect
– Large scale production at
lowest cost
– Easiest and cheapest to
package and ship
– High stability
• User aspect (doctor,
pharmacist, patient)
– Easy to handling
– Lightest and most compact
– Greatest dose precision &
least content variability
Disadvantages
• Some drugs resist
compression into dense
compacts
• Drugs with poor wetting, slow
dissolution, intermediate to
large dosages may be difficult
or impossible to formulate and
manufacture as a tablet that
provide adequate or full drug
bioavailability
• Bitter taste drugs, drugs with
an objectionable odor, or
sensitive to oxygen or moisture
may require encapsulation or
entrapment prior to
compression or the tablets
may require coating
Types of tablets
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1)compressed tablets
2)sugar coated tablets
3)film coated tablets
4)enteric coated tablets
5)effervescent tablets
6)chewable tablets
7)dispersible tablets
8)sustained release tablets
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9)multilayer tablets
10)sublingual tablets
11)toroches
12)buccal tablets
13)implant tablets
14)hypodermic tablets
15)solution tabletc
16)vaginal tablets
EXCIPIENTS FOR COMPRESSED
TABLETS
Compressed tablets usually contain a number of
pharmaceutical adjuncts, known as excipients, in addition
to the medicinal substance. The use of appropriate
excipients is important in the development of the optimum
tablets. Excipients determine the bulk of the final product
in dosage forms such as tablet, capsule, etc., the speed
of disintegration, rate of dissolution , release of drug,
protection against moisture, stability during storage, and
compatibility . Excipients should have no bioactivity, no
reaction with the drug substance, no effect on the
functions of other excipients, and no support of
microbiological growth in the product .
A. DILUENTS
Diluents increase the volume to a formulation to
prepare tablets of the desired size. Widely used
fillers are lactose, dextrin, microcrystalline cellu-
lose starch, pregelatinized starch, powdered
sucrose, and calcium phosphate.
• The diluent is selected based on various factors, such as
the experience of the manufacturer in the preparation of
other tablets, its cost, and compatibility with other
formulation ingredients. For example, in the preparation
of tablets or capsules of tetracycline antibiotics, a
calcium salt should not be used as a diluent since
calcium interferes with absorption of the antibiotics from
the GI tract.
B.BINDERS
• Binders promote the adhesion of particles of the
formulation. Such adhesion enables preparation of
granules and maintains the integrity of the final tablet.
As listed in the Table, Commonly used binding agents
include: starch, gelatin and sugars (sucrose, glucose,
dextrose, and lactose).
Examples of Binders
Carboxymethylcellulose, sodium
Karaya gum
Cellulose,microcrystalline(Avicel®) Starch, pregelatinized
Ethylcellulose
Tragacanth gum
Hydroxypropyl methylcellulose
Poly(acrylic acid)
Methylcellulose
Polypvinylpyrrolidone
Acacia gum
Gelatin
Agar
Dextrin
Algin acid
Glucose
Guar gum
Molasses
C. LUBRICANTS
• Lubricant is a substance capable of reducing or
preventing friction, heat, and wear when introduced as a
film between solid surfaces. It works by coating on the
surface of particles, and thus preventing adhesion of the
tablet material to the dies and punches.
Glycerylmonostearate(USP/NFCH2(OH)CH(OH)CH2O2
CC17H35) is one example of a lubricant. Lubricants play
more than one role in the preparation of tablets as
described below.
• 1. Lubricants improve the flow of granules in the hopper
to the die cavity.
• 2. Lubricants prevent sticking of tablet formulation to the
punches and dies during formulation.
• 3. Lubricants reduce the friction between the tablet and
the die wall during the tablet’s ejection from the tablet
machine.
• 4. Lubricants give a sheen to the finished tablets.
• Commonly used lubricants include: talc,
magnesium stearat, calcium stearate ,stearic
acid, hydrogenated vegetable oils and (PEG).
D. DISINTEGRATORS
•
The breakup of the tablets to smaller particles is important for
dissolution of the drug and subsequent bioavailability.
Disintegrators promote such breakup. To rupture or breakup of
tablets, disintegrating agents must swell or expand on exposure to
aqueous solution. Thus, the most effective disintegrating agents in
most tablet systems are those with the highest wa-ter uptake
property. In general, the more hydrophilic, the better disinte-
grating agents are therefore highly hydrophilic. A list of typical
disinte-grants is tabulated in Table
E. WETTING AGENTS
• Water molecules attract each other equally in all directions. Water
molecules on the surface, however, can only be pulled into the bulk
water by water molecules underneath, since there are no water
molecules to pull in the opposite direction. The surface tension of
water is strong enough to support the weight of tiny insects such as
water striders. The surface ten-sion in action can be visualized by
placing a small drop of alcohol on a thin layer of water. Alcohol with
lower surface tension mixes with water causing reduction in the
surface tension in the local region. Owing to the higher surface
tension of water in the neighbor, water is pulled from the alcohol
dropped region into the neighbor, and this leads to the formation of a
dry spot in the middle of the water layer.
Compressed tablet manufacture
•The classification of manufacturing methods
granulation
wet granulation: suitable for drugs that are stable to moisture
and heat
dry granulation: suitable for drugs that are sensitive to
moisture and heat
powder compression : suitable for drugs that are sensitive
to moisture and heat, fill material possessing, good flowability
direct
compression and compressibility
crystal compression：suitable for drugs with proper
crystal form and good flowability
wet granulation
adhesive
drug
prilling
sieving
excipients
lubricant
dry
processing
granule
mix
press
dry granulation
adhesive
drug
smash
excipient
mix
press
sieving
mix
press
cake
processing
smash
granule
powder compression
adhesive
drugs
smash
excipients
sieving
mix
mix
press
• crystal compression
drugs
smash
adhesive
sieving
mix
excipients
mix
press
• wet granulation technology
• (一)wet granulation methods and equipment:
• 1.Extrusion grain methods and equipment: first
prescription drug powder and the auxiliary materials
mixed evenly to join adhesive soft material system, then
with soft material compulsory extrusion way through has
a certain size screen hole and granulating method.
wet granulation
Compressed tablet manufacture
—— wet granulation
• The steps of wet granulation
weighing and blending the ingredients(disintegrant)
(liquid binder)
preparing a damp mass
Internal(内加法)
screening the damp mass into pellets or granules
drying the granulation
sizing the granulation by dry screening
adding lubricant and disintegrant, and blending
tableting by compression
External(外加法)
The classification of tablet presses
• Tablet presses:
a. single-punch presses
b. multi-station rotary presses
The main components of single-punch
tablet presses
Core components:
die
lower punch
upper punch
The basic mechanical process of tableting
with single-punch presses
a) filling material
b) scraping away the excessive
granulation
c) forming a tablet by compression
d) pushing up the tablet to stage
surface
e) shoving the tablet aside
A picture of multi-station rotary press
hopper
feed-frame
head: upper turret, lower turret, die table
upper turret
die table
lower turret
The core components and compression
cycle of rotary presses
A: upper punch
B: die cavity
C: die
D: lower punch
The compression
is applied by both
the upper punch
and the lower
punch.
The compression cycle of a rotary tablet press
Compressed tablet manufacture
—— Direct compression tableting
Suitable for
1) granular chemicals possessing free flowing and
cohesive properties
e.g. potassium chloride
2) chemicals added with special pharmaceutical
excipients which impart the necessary qualities for the
production of tablets by direct compression
The direct compression tableting excipients include:
a) fillers, as spray-dried lactose, microcrystals of alphamonohydrate
lactose, sucroseinvert ,sugar – corn starch mixtures, microcrystalline
cellulose, crystalline malt and dicalcium phosphate;
d) disintegrants, as direct-compression starch, sodium carboxymethyl
starch, cross-linked carboxymethylcellulose fiber, and cross-linked
polyvinylpyrrolidone;
c) lubricants, as magnesium stearate and talc;
d) glidants, fumed silicon dioxide
• Sophora Alopecuruldes L．Seed Tablet
optimization
excipient
powder of sophora
AIopecuroides L． Seed
press
1％Magnesium
stearate
mix
制软材
prilling 、
processing
granule
mix
table 1
the influence of different adhesive to Tablet hardness
formula
1
adhesive
10%
Starch
Hardness
（Kg）
0.68
2
10%PVP
（water）
0.83
3
10%CMC-Na
0.75
4
10%PVP
(Ethanol)
particles
deformed
table 2
the influence of different fillers to Tablet hardness
formula
5
6
7
fillers
starch
Pregelati lactose
nized
starch
Hardnes
s（Kg）
0.68
0.77
3.14
8
10%PVP
( Ethanol)
3.55
table 3 factor level
Factor
level
A [The amount of Microcrstalline
cellulose(g)]
80
120
160
A [Concentration of PVP
solution（%，g/ml)]
10
15
20
table 4 Result of Orthogonal test
A×B
Test NO.
1
2
3
4
5
6
7
8
9
K1
K2
K3
A
B
1
1
1
2
2
2
3
3
3
17.8
24.2
24.4
1
2
3
1
2
3
1
2
3
23.0
21.8
21.6
1
2
1
2
3
2
3
1
3
1
2
21.4
22.5
22.5
1
2
3
3
1
2
2
3
1
22.2
22.0
22.2
1.1
R×6
6.6
1.4
Result
0.2
0.6
Ⅰ
Ⅱ
3.1
2.8
3.2
4.1
4.0
4.2
4.0
3.9
2.9
3.1
2.7
4.4
4.1
3.4
3.8
4.2
Total
6.0
5.9
5.9
8.5
8.1
8.5
7.8
8.1
table5
variance source
SS
total variance
5.658
A
Analysis of variance table
V
MS
F
P
4.698
2
2.349
33.562
0.0001
B
0.191
2
0.096
1.366
0.3034
A×B
0.139
4
0.035
0.993
0.4077
error
0.630
9
0.070
table６
微晶纤维素用量影响苦豆子片硬度的ｑ检验（ｎ＝６）
Comparison 两均数之
group
差
standard
value of q Number
ｑ界值
error
of
group
α =0.05
α= 0.01
A1andA3
-1.1
0.1074
-10.241
3
4.34
6.33
<0.01
A1andA2
-1.0
0.1074
-9.310
2
3.46
5.24
<0.01
A2andA3
-0.1
0.1074
-9.310
2
3.46
5.24
>0.05
P
Tablet coating
The reasons for tablet coating
1) to protect the medicinal agent against destructive exposure to air
and/or humidity;
2) to mask the taste of the drug;
3) to provide special characteristics of drug release;
4) to provide aesthetics or distinction to the product;
5) to prevent inadvertent contact by nonpatients with the drug
substance
The general methods involved in coating tablets are as follows
1) sugarcoating tablets
2) film-coating tablets
3) enteric coating
4) pan coating
5) fluid-bed or air suspension coating
6) compression coating
The sugarcoating of tablets may be divided into the
following steps:
1) waterproofing and sealing (if needed)
2) subcoating
3) smoothing and final rounding
4) finishing and coloring (if desired)
5) polishing
片芯 ——包层隔离——包粉衣层——包糖衣层——包有色糖衣层——打光
film-coating machine
1) waterproofing and sealing (if needed)
aim: to prevent the components from being adversely
affected by moisture; one or more coats; shellac , zein ,
or a polymer as cellulose acetate phthalate
2) Subcoating aim: to bond the sugar coating to the tablet
and provide rounding
a) 3 to 5 subcoats of a sugar-based syrup are applied.
The sucrose and water syrup also contains gelatin,
acacia, or PVP.
b) When the tablets are partially dry they are sprinkled with
a dusting powder, usually a mixture of powdered sugar
and starch but sometimes talc, acacia, or precipitated
chalk as well.
c) Then drying the tablets. Repetition (15 to 18 times) the
subcoating process until the tablets are of the desired
shape and size.
3) smoothing and final rounding
aim: to complete the rounding and smooth the coatings
5 to 10 additional coatings of a thick syrup; This syrup is
sucrose-based with or without additional components as
starch and calcium carbonate.
4) finishing and coloring
aim: to attain final smoothness and the appropriate color
several coats of a thin syrup containing the desired colorant
5) imprinting
aim: to impart identification codes and other distinctive symbols to the
product
The imprint may be debossed, embossed, engraved, or printed on the
surface with ink.
6) polishing
aim: to render the tablets the desired sheen/gloss/luster
a) pans lined with canvas cloth impregnated with carnauba waxand/or
beeswax
b) Pieces of wax may be placed in a polishing pan
c) light-spraying of the tablets with wax dissolved in a nonaqueous
solvent
Tablet coating
—— film-coating tablets
1) The disadvantages of sugarcoating process
a) time-consuming
b) requiring the expertise of highly skilled technicians
c) doubling the size and weight of the original uncoated tablets
d) may vary in size from batch to batch and within a batch
e) large tablets are not as easily swallowed as are small tablets.
2) The advantages of film-coating process
a) coated tablets having essentially the same weight, shape, and size
as the originally compressed tablet
b) The coating is thin enough to reveal any identifying monograms.
c) far more resistant to destruction by abrasion than are sugar-coated
tablets
d) the coating may be colored to make the tablets attractive and
distinctive.
3) The components of nonaqueous film-coating solutions:
a) film former: e.g. CAP
b) alloying substance: to provide water solubility or permeability to
the film e.g. PEG
c) plasticizer: to render flexibility and elasticity to the coating e.g.
castor oil
d) surfactant: to enhance spreadability of the film e.g.
polyoxyethylene sorbitan derivatives
e) opaquants and colorants: e.g. titanium dioxide, FD&C or D&C
dyes
f) sweeteners, flavors, and aromas: saccharin, vanillin
g) glossant: beeswax
h) volatile solvent: alcohol-acetone mixture
4) The components of a typical aqueous film-coating
solutions:
a) film-forming polymer (7-18%): e.g. cellulose ether
polymers as HPMC, HPC and MC
b) plasticizer (0.5-2.0%): e.g. glycerin, propylene glycol,
PEG, diethyl phthalate, and dibutyl subacetate
c) colorant and opacifier (2.5-8%): FD&C or D&C lakes
and iron oxide pigments
d) water
5) Some problems with aqueous film-coating
a) picking and peeling
the appearance of small amounts or large
amounts of film fragments flaking from the tablet surface
b) orange peel effect
roughness of the tablet surface due to failure of
spray droplets to coalesce
c) mottling
an uneven distribution of color on the tablet surface
d) bridging
filling-in of the score-line or indented logo on the tablet by the film
e) tablet erosion
disfiguration of the core tablet
5) Some problems with aqueous film-coating
a) picking and peeling
the appearance of small amounts or large
amounts of film fragments flaking from the tablet surface
b) orange peel effect
roughness of the tablet surface due to failure of
spray droplets to coalesce
c) mottling
an uneven distribution of color on the tablet surface
d) bridging
filling-in of the score-line or indented logo on the tablet by the film
e) tablet erosion
disfiguration of the core tablet
The reasons for capping,
splitting or laminating of
tablets
1) air entrapment
2) not immaculately cleaned or not perfectly
smoothed punches
3) too great a proportion of fine powder
4) Tablets have aged or have been stored
improperly
quality standards and compendial
requirements
The apparent physical features of compressed tablets:
1) shape: round, oblong, unique
2) thickness: thick or thin
3) diameter: large or small
4) flat or convex
5) unscored or scored in halves, thirds and quadrants
6) engraved or imprinted with an identifying symbol and/or code
number
7) coated or uncoated 8)colored or uncolored 9) number of layer.
The die and punches determine the physical features of compressed
tablets.
quality standards and compendial
requirements
 Other physical specifications and quality standards:
tablet weight
weight variation
content uniformity
tablet thickness
tablet hardness
tablet disintegration
drug dissolution
 in-process controls
 verification after the production
quality standards and compendial requirements
—— tablet weight and Chp weight variation
 Chp weight variation:
sample amount 20 tablets
 Tablets should comply
with the following
Average
weight
Weight
variation
limit
Less than
0.3 g
± 7.5%
0.3 g or
more
± 5%
requirements stated in
the table below.
电子称量仪
quality standards and compendial requirements
—— tablet weight and Chp weight variation
The procedure of weight variation determination in Chp:
Weigh accurately 20 tablets and calculate the average
weight, then weigh individually each of the 20 tablets.
Compare the weight of each tablet with the labelled
tablet (if no labelled weight is stated, compare the weight
of each tablet with the average weight calculated). No
more than 2 of the individual weights exceed the weight
variation limit stated in the table above and none doubles
the limit.
quality standards and compendial requirements
—— tablet hardness and friability
Tablet hardness
1)The greater the pressure applied, the harder the tablets.
2) The hardness required by different tablets
a) lozenges and buccal tablets: hard (dissolve slowly)
b) the tablets for immediate drug release: soft
3) measurement
a) special dedicated hardness testers
b) multifunctional equipment
quality standards and compendial requirements
—— content uniformity
 applys to potent drug of low dose.
 USP method, 10 tablets are individually assayed for their
content.
The amount of active ingredient in each tablet lies within
the range of 85% to 115% of the label claim and the
RSD is less than 6.0%.
quality standards and compendial requirements
—— tablet hardness and friability
(continued)
Friability
1) It is used to determine a tablet’s durability
2) Method: allowing the tablets to roll and fall within the
rotating apparatus (friabilator); determine the loss in
weight;
3) requirement: weight loss ≤1%
硬度检测仪
片剂脆碎度检测仪
溶出仪
自动溶出取样机
quality standards and compendial requirements
—— tablet dissolution
1) The importance of in vitro dissolution test
a) to guide the formulation and product development
process toward product optimization
b) to monitor the performance of manufacturing process
c) to assure bioequivalence from batch to batch
d) as a requirement for regulatory approval for product
marketing for products registered with the FDA and
regulatory agencies of other countries.
2) The goal of in vitro dissolution is to provide a
reasonable prediction of the product’s in vivo
bioavailability.
Basis: The combinations of a drug’s solubility and
its intestinal permeability are supposed as a
basis for predicting the likelihood of achieving a
successful in vivo – in vitro correlation (IVIVC).
Considered are drugs determined to have:
a) high solubility and high permeability (IVIVC
may be expected.)
b) low solubility and high permeability (IVIVC
may be expected.)
c) high solubility and low permeability
d) low solubility and low permeability
3) The formulation and manufacturing factors
affecting the dissolution of a tablet
a) the particle size of the drug substance
b) the solubility and hygroscopicity of the
formulation
c) the type and concentration of the disintegrant,
binder, and lubricant used
d) the manufacturing method, particularly, the
compactness of the granulation and the
compression force
e) the in-process variables
4) Test method
a) A volume of the dissolution medium is placed in the
vessel and allowed to come to 37℃±0.5℃.
b) The stirrer is rotate at the specified speed.
c) At stated intervals, samples of the medium are
withdrawn for chemical analysis
5) Requirement for rate of dissolution
The specific required rates of dissolution are different for
tablets containing different medicinal agents.
e.g. not less than 85% of the labeled amount is dissolved
in 30 minutes
6) Inconsistencies in dissolution
occur not between dosage units from the same production
batch, but rather between batches or between products
from different manufacturers.
Pooled dissolution testing has emerged. This process
recognizes the concept of batch characteristics and
allows pooled specimens to be tested.