Module 10 Flashcards
The development in the field of APIs, excipients and _______ machines during the past decades has made _______ manufacturing a science and the ______ the most commonly used dosage form.
tablets
The ease of manufacturing, convenience in administration, accurate dosing, and
stability compared to oral liquids, tamper-proofness compared to capsules, safe
compared to parenteral dosage forms makes it a popular and versatile dosage form.
tablets
Tablets have been produced for more than 150 years. The first tableting machine, developed
by ________ in 1972, was a manually operated ___________.
Brockedon; single - punch machine
Currently high - speed tableting machines can produce more than a _________ tablets per hour.
million
________ can be defined as any machine capable to produce tablets.
Tablet production systems
They include tableting machines for production and research as well as _________ which are able to mimic the production processes of
tableting machines of different size and velocity in order to facilitate scale - up.
tableting machine simulators
The amount of drug in the _____ of development still makes the use of small tableting machines necessary.
early stages
Thus, before final production a _____ from small machines useful for the production of single tablets to high - speed machines is
necessary.
scale - up
Not all pharmaceutical ingredient is capable of _________.
compression
Excellent properties for compression
AR: 25 - 30
CI: <10
HR: 1.00 - 1.11
Good properties for compression
AR: 31 - 35
CI: 11-15
HR: 1.12 - 1.18
Fair properties for compression
AR: 36 - 40
CI: 16-20
HR: 1.19 - 1.25
Passable properties for compression
AR: 41 - 45
CI: 21-25
HR: 1.26 - 1.34
Poor properties for compression
AR: 46 - 55
CI: 26-31
HR: 1.35 - 1.45
Very poor properties for compression
AR: 56 - 65
CI: 32-37
HR: 1.46 - 1.59
Very very poor properties for compression
AR: >66
CI: >38
HR: >1.60
Three well known methods for tablet manufacturing
- Wet-granulation
- Dry-granulation (roller compaction)
- Direct compression
________ is the process of particle enlargement by agglomeration technique.
Granulation
It is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules.
Granulation
Granulation process transforms fine powders into _______ granules
that are easy to compress.
free-flowing, dust-free
Granulation poses numerous challenges due to high quality requirement of the formed
granules in terms of: (2)
- content uniformity; and
- physicochemical properties such as granule size, bulk density, porosity, hardness,
moisture, compressibility, etc. together with physical and chemical stability of the
drug.
Granules are produced: (5)
- to enhance the uniformity of the API in the final product,
- to increase the density of the blend so that it occupies less volume per unit weight for
better storage and shipment, - to facilitate metering or volumetric dispensing,
- to reduce dust during granulation process to reduce toxic exposure and process-
related hazards, and - to improve the appearance of the product.
The ideal characteristics of granules include (4)
- spherical shape for improved flow,
- narrow particle size distribution for content uniformity and volumetric dispensing,
- sufficient fines to fill void spaces between granules for better compaction and
compression characteristics, and - adequate moisture and hardness to prevent breaking and dust formation during
process.
The most widely used process of agglomeration in the pharmaceutical industry.
Wet granulation
Wet granulation process involves wet massing of the powder blend with a __________.
granulating liquid
______ is used a granulating liquid (e.g., ethanol, isopropanol, other
alcohol aqueous solutions).
Volatile solvent
Wet granulations steps
- Spraying (binder droplets and powders)
- Moistening (liquid bridge)
- Solidifying (solid bridge)
- Finished agglomerate (snowball structure)
Important steps involved in wet granulation (5):
i) Mixing of the drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form wet mass
iv) Drying of moist granules
v) Mixing of screened granules with disintegrant, glidant, and lubricant
Advantages of wet granulation (8)
(a) permits mechanical handling of powders without loss of mix quality;
(b) improves the flow of powders by increasing particle size and sphericity;
(c) increases and improves the uniformity of powder density;
(d) improves cohesion during and after compaction;
(e) reduces air entrapment;
(f) reduces the level of dust and cross-contamination;
(g) allows for the addition of a liquid phase to powders (wet process only); and
(h) Makes hydrophobic surfaces hydrophilic.
Limitations of wet granulation (5)
i) The greatest disadvantage of wet granulation is its cost. It is an expensive process
because of labor, time, equipment, energy and space requirements.
ii) Loss of material during various stages of processing.
iii) Stability may be major concern for moisture sensitive or thermo labile drugs.
iv) Multiple processing steps add complexity and make validation and control difficult.
v) An inherent limitation of wet granulation is that any incompatibility between
formulation components is aggravated.
_____ or ______ is a new development in the wet granulation technique that involves the immersion of the dry powder formulation into the binder liquid followed by controlled breakage to form granules.
Reverse wet granulation; reverse-phase wet granulation
The advantages of reverse wet granulation over conventional wet granulation include small
and _______ granules with improved __ properties, uniform wetting and erosion of the granules.
spherical-shaped; flow
This technique could be suitable for_______drugs because of the intimate association between a drug and the polymer.
poorly water-soluble
In ________ as a new wet granulation technique, water steam is used as binder instead of
traditional liquid water as granulation liquid.
steam granulation
The advantages of steam granulation include the higher ability of the steam to distribute uniformly and diffuse into the powder particles, production of
spherical granules with _____, and shorter processing time, eco-
friendly (no involvement of _____).
larger surface area; organic solvents
________, spray freezing and subsequent freeze drying, involves spraying droplets of a liquid slurry or suspension into liquid nitrogen
followed by freeze-drying of the frozen droplets.
Freeze granulation technology
By spraying a powder suspension into ________, the drops are instantly frozen into granules, and
in the subsequent freeze drying process, the granules are dried by _______ of ice without any
segregation effects.
liquid nitrogen; sublimation
In ________ process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation.
dry granulation
The two basic procedures are to form a compact material by _________ and then to _____ the compact to obtain granules.
compression; mill
The more widely used method for dry granulation is _____, where the powder is recompressed and the
resulting tablet or _______ are milled to yield the granules.
slugging; slug
The other method is to ______ the powder with pressure rolls using a machine such as _________.
precompress; Chilosonator (Roller compaction)
Unlike a tablet machine, the chilsonator turns out a
compacted mass in a steady _______ flow.
continuous
The powder is fed down between the rollers from the hopper which contains a spiral ______ to feed the powder into the _________.
auger; compaction zone
Like ______, the aggregates are screened or milled for production into granules.
slugs
Used in the production of directly compressible excipients, the compaction of drugs
and drug formulations, the granulation of inorganic materials, the granulation of dry
herbal materials, and the production of immediate/sustained release formulations.
Roller compaction
The main advantages of dry granulation or slugging are that it uses less ____ and _____.
equipments; space
Dry granulation eliminates the need for _______ solution, heavy mixing equipment and the costly
and time consuming drying step required for _____.
binder; wet granulation
Slugging can be advantageous in the following situations (3):
○ For moisture sensitive material
○ For heat sensitive material
○ For improved disintegration since powder particles are not bonded together by a binder
Disadvantages of dry granulation (4)
i) It requires a specialized heavy duty tablet press to form slug
ii) It does not permit uniform colour distribution as can be
iii) Achieved with wet granulation where the dye can be incorporated into binder
liquid.
iv) The process tends to create more dust than wet granulation, increasing the
potential contamination.
An innovative dry granulation technology which utilizes roller compaction together with a
proprietary air classification method to produce granules with extraordinary combination of flowability and
compressibility.
Pneumatic dry granulation (PDG),
This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed.
Direct compression
This is not very common method because many tablets have active pharmaceutical ingredients due to their concentration or the excipients used in formulation are not conducive to this method.
Direct compression
The prime advantage of direct compression over wet granulation is economic since the direct
compression requires _________. This means less equipment, lower power consumption, less
space, less time and less labor leading to reduced production cost of tablets.
fewer unit operations
Direct compression is more suitable for _________ and ______ sensitive APIs, since it eliminates wetting and drying steps and increases the stability of active ingredients by reducing detrimental effects.
moisture; heat
Changes in ______ are less likely to occur in tablets made by direct compression on storage than in
those made from granulations. This is extremely important because the __________ now requires dissolution specifications in most solid dosage forms.
dissolution profiles; official compendium
__________ is the rate limiting step in absorption in the case of tablets of __________ API prepared by wet granulation.
Disintegration or dissolution; poorly soluble
The tablets prepared by direct compression disintegrate into_________ instead of granules that directly come into contact with _________ and exhibits
comparatively faster dissolution.
API particles; dissolution fluid
The high compaction pressure involved in the production of tablets by _______ can be avoided by adopting direct compression. The chances of wear and tear of punches and dies are less.
slugging or roller compaction
Due to ________ of direct compression, materials are “in process” for a shorter period of time, resulting in less chance for contamination or cross contamination, and making it easier to meet the requirement of current good manufacturing practices. Due to fewer unit operations, the validation and documentation requirements are reduced.
simplified validation
Due to the absence of ______ in granulation, chance of microbial growth is minimal in tablets prepared by direct compression.
water
Direct compression is more prone to ________ due to the difference in density of the API and excipients. The dry state of the material during mixing may induce _________ and lead to ___________.
This may lead to the problems like weight variation and content uniformity.
segregation; static charge; segregation
Cost: _____________ are the specialty products produced by patented spray drying, fluid bed drying, roller drying, or co-crystallization. Hence, the products are relatively costly than the respective raw materials.
Directly compressible excipients
Low dilution potential: Most of the directly compressible materials can accommodate only ________ of the poorly compressible
active ingredients like acetaminophen that means the weight of the final tablet to deliver the 500 mg of acetaminophen would be more than 1300 mg. The large tablets may create difficulty in swallowing.
30-40 %
Re-workability: All the _______ show poor rework ability since on preparation of tablets the original spherical nature of the excipient particles is lost. API that has poor flow properties and/or low bulk density is difficult to process by direct compression.
spray-dried directly compressible adjutants
_________ have a more adverse effect on the filler, which exhibit almost no fracture or shear on
compression (e.g. starch 1500). The softening effects as well as the _________ effect of alkaline
stearates can be controlled by optimizing the length of blending time to as little as 2-5 min.
Lubricants; hydrophobic
There is a lack of awareness in some situations that the excipient behave differently, depending upon the vendor so much so that substitution from one source to that of another is not possible. Hence, there is a need for greater _________ in purchasing of raw material to assure batch uniformity.
quality control
__________ modification is not preferred to a greater extent as it results in the formation of an altogether new chemical entity. One has to submit ________ data for the new compound, which is quite
cumbersome, time consuming, and relatively expensive.
Chemical; toxicological
________modification is relatively simple and economical. The addition of _________ of similar structure to alter the crystal structure i.e. Dextrates or compressible sugar, i.e., Dicalcium phosphate, sorbitol.
Physical; impurities
The purpose of ______ or ______ materials for direct compression is primarily to control flow properties. The compressibility may also get altered because of changes in particle properties such as surface _____ and surface ______.
sieving; grinding; area; activation
Controlled _______ would impart flowability to an excipient but not necessarily _____________
properties. The conditions of crystallization determine to a large extent the solid-state properties of
directly compressible excipients.
crystallization; self-binding
Spray drying involves ______ of the aqueous solution or suspension into a spray. Contact between the spray and _____ in a drying chamber results in moisture evaporation and recovery of the dried product from the air.
atomization; hot air
Because of the ______ nature of liquid particles after evaporation of water, the resulting spray-dried
material consist of porous spherical agglomerates of solid particles that are fairly uniform size in the ______ component generated by rapid cooling and crystallization act as a binder.
spherical; amorphous
The atomization process, the drying chamber cooling rate, and rate of crystallization are the major factor that govern the ____ and _____ of the spray- pharmaceutical ingredient to successfully exemplify the spray drying
technology.
shape; size
________ and ________ represent the transformation of small, cohesive, poorly flowable
powders into a flowable and directly compressible from. Granulation results in nearly spherical particles
with relatively high ________ and strength.
Granulation; agglomeration; bulk density
________ on the other hand, leads to irregularly shaped porous particles with relatively ____ bulk
density and strength. When the primary panicles have binding properties of their own, the addition of ____ is not necessary.
Agglomeration; low; binder
_____ is the combination of two or more excipients to form materials (coprocessed _______ ) of superior functionality and limited unwanted effects.
Coprocessing; excipients
_________ is a process by which the molecular interactions can be altered to optimize the drug properties.
Co-crystallization
In co-crystallization, co-crystals comprise a multicomponent system of active pharmaceutical ingredient (API) with a stoichiometric amount of a pharmaceutically acceptable coformer incorporated in the _______.
crystal lattice
_______ and _______ are tools that is employed by pharmaceutical
ingredient manufacturers and formulation scientists to develop materials with superior
performance.
Co-processing; co-crystallization
_______ is defined as a technique of applying coating material to the
external surface of the tablet core.
Tablet coating
Tablet coating is the process of a coating composition to a moving bed of tablets with the
concurrent use of ________ to facilitate evaporation of solvent
heated air
Tablet coating process is considered as one of the oldest arts in pharmaceutical sciences. Started in the _____ century by coating pills to mask unwanted _____.
17th; taste or odor
Tablet coating process is also used for the following purposes:
○ Control release of drug from the tablet
○ Offer physical and chemical protection to the drug
○ Minimize product damage due to physical stress
○ Protect stomach from adverse effects of the drug
○ Protect drug from the gastric environment of the stomach
○ Improve pharmaceutical elegance
○ Improve product appearance and help in brand identification
○ Masking batch differences in the appearance of raw materials
Main types of coating
- Film coating
- Sugar coating
- Press coating
- Functional coating
Modern approach to coating tablets, capsules, or pellets by surrounding
them with a thin layer of polymeric
material
Film coating
Film coating is a ______ stage process, which involves spraying a coating solution or suspension
single
Film coating advantages (6)
- Single step process
- Minimal weight increase (~3%)
- The film is very thin
- Engravings are possible on tablet surface
- Better mechanical strength is obtained
- Cost efficient
Film coating disadvantages (2)
- Use of organic solvent
- Less appeal to consumer due to tasteless nature
The traditional method of coating tablets which involves the successive application of sucrose-based solutions to tablet cores
Sugar coating
Sugar coating advantages (3)
- Masks unwanted taste, odor, or color
- Protects drug from air and moisture
- Improve appearance of tablet or capsule (due to glossy appearance of the sugar
coat)
Sugar coating disadvantages (4)
- Time consuming process
- High weight gain
- Increase cost in packaging and shipping
- Imprinting problems
Film coating retains the contour of original core while sugar coating is _______ with high degree of ________.
rounded; polish
There is a _________% weight increase of coating material in film coating against a sugar coating for ______%.
2-3; 30-50
Logo or break lines is possible for
Film coating
Film coating involves a ________ stage(s) while sugar coating involves ____________ stage(s).
single; multistage
Film coating typically needs ______ hrs of coating time while sugar coating needs _________ or longer.
1.5 - 2; 8
Film coating has easily adaptable functional coatings for controlled release while this is not possible for sugar coating apart from _______ coating.
enteric
Involves the compaction of granular material around an already preformed core
using compressive equipment similar to that used for the core itself.
Press coating
Tablet coatings that perform a pharmaceutical function (i.e., control or enteric
release)
Functional coating
Specialized coating processes (3)
- Dip coating
- Electrostatic coating
- Vacuum film coating
