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3072132001 Drug Delivery I.doc

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					30:721:320:01 Drug Delivery I
          Class Outline
Professor John L. Colaizzi, Ph.D.
          January 29, 2009

                                               Solid Pharmaceutical Dosage Forms: TABLETS

Definition of Tablets:
Solid dosage form either compressed or molded.

Reasons for the popularity of tablet dosage forms:
    1. low cost to manufacture
    2. represent a stable dosage form , chemical, physical, microbial
    3. ease of administration
    4. accuracy of dosage
    5. ease of packaging and portability
    6. relatively tamper resistant than capsules
    7. provide ease of identification with logos


Bioavailability considerations with tablet dosage forms:
High pressure is used to compress  can be resistant to disintegration  dissolution process
Potential dosage forms that could lead to bioavailability problems
Certain excipients can cause issues of bioavailability


Quality Control and Quality Assurance (QC & QA) considerations with tablet dosage forms:

Each step needs to be manufactured with quality control and quality assurance tests.


          ● Process Validation –the final step in the quality assurance process
all of the steps together do produce a quality product – uniform quality- can’t have variation from one
tablet to another or by batch


Historical evolution of tablet dosage forms:

         ● Pills – round solid dosage forms that were prepared from a doughy mass. Able to be
compounded by the pharmacist and roll into little balls and let them dry. Pill has been taken to apply to any
solid dosage forms, ie tablets and capsules. Was once a forerunner of these.

          ● Molded Tablets (Tablet Triturates; “Hypodermic Tablets”)
Trituration process when mixed in mortar and pestle
If you have to make tablets in the compounding pharmacy today (extemporaneous tablets)  use molded
 usually a metal or plastic plate Molded tablets involve no compression  suitable for extemporaneous
cmpnding.
Made of soluble ingredients, even excipients  referred to has hypodermic tablets, doctors carry around in
bag then would dissolve them and give injections




         ● Compressed Tablets
The majority of tablets are referred to these, prepared industrially
Tablets were invented as a compressed dosage form in 1878 in England and were introduced as a “tablet”
Introduced to the US in 1892, Burrs Welkin  Glaxo Smith Kline  Wyath (Madison, NJ), Phizer just
bought it?


        ● Calculation example for compounding of Tablet Triturates –

Prepare 50 tablets each containing 2.2 mg NaF. Use a tablet base consisting of 20% sucrose and 80%
Lactose (Hydrous).

Prepare a small test batch of base: 200 mg sucrose + 800 mg Lactose. Mix. Moisten with a solution of 7.5
mL USP Alcohol (95%) qs 10 mL water.
Add the solution drop by drop in glass m&p until the test batch has consistency of play-dough or modeling
clay. Uniformly fill the holes on a tablet triturate mold plate. Place the mold plate onto the pegs, and
gently push down until the tablets are sitting on top of the pegs. Allow to air dry. Gently remove the test
tablets and weigh. If each test tablet weighs 60 mg, calculate as follows:
          Each tablet will consist of 2.2 mg NaF + 57.8 mg base. For 50 tablets: 110 mg NaF + 2890 mg
base

        0.2 X 2890 mg = 578 mg sucrose                         0.8 X 2890 mg = 2312 mg Lactose
(Hydrous)/

Mix 110 mg NaF + 578 mg sucrose + 2312 mg Lactose geometrically. Moisten drop by drop with the
ethanol-water mixture.
Proceed to prepare 50 tablets using the same technique as for the preparation of the test tablets.

Will always lose some, should prepare for 55 to make 50
                    (p.1)


Compressed Tablets
Shapes and sizes of tablets:       Grooved (Scored)          Discoid         Thickness (height)
Refer to other handout
Do not want to make them too big because many have difficult time swallowing
Children and elderly
The bases of these punches can have engravings to imprint name/number to identify the tablets
The tablet thickness has to be carefully controlled during manufacturing process  cannot vary by more or
less than 5%
When these tablets are counted in the automatic counting devices


Compressed Tablets - General considerations:
   1. the formulation and production of these products is relatively complex and challenging , industrial
       formation
       by messing up the process, the bioavailability and other components can be easily messed up
   2. These tablets in which the active drug occupies a high percent of weight of tablet are more
       challenging to make. Easier when the largest component of the weight consists of the excipient,
       proper compressibility ,
   3. infinite number of shapes and sizes changes of punches and dies  flexible dosage form


Coated Tablets; Uncoated Tablets:                  Imprinting                             Embossing
(Engraving)
If they are coated, you put logos by the process of imprinting
If uncoated then embossing or engraving is used  in the face of the punch
Coating  additional cost factor and cal also add weight, makes tablet easier to swallow and can mask any
unpleasant taste or odor
Original kind of coating was sugar coating, now film coating  advantage of film is that it is much thinner,
does not add dimension or weight, less likely to chip or crack

Multiple Compressed Tablets:
Tablets that go through more than one compressing cycle
Reason would be to separate incompatible ingredients, chemically or physically incompatible, to give it a
unique experience, or to provide a type of controlled release
An internal tablet invisible, outer layer is first dose, and delayed release dose in the middle
A tablet within a tablet  dry coated tablet , where the external tablet is in a sense a coating

         ● Layered Tablets


         ● Press-Coated Tablets /dry coated


Specialized Tablets:

          ● Controlled (Extended) Release Tablets –
Original is the Enteric Coated tablet, a coating called salol  would not release in the acidic environment
of the stomach, but in the small intestine, this was to deal with drugs that were acid-labile
Controlled release has come a long way since then  have been available for about 50/60 years, introduced
in the 1950s

          ● Effervescent Tablets –
tablets that are formulated (alka seltzer) with sodium bicarbonate and an organic acid such has tartaric acid
or citric acid
if you put these in water, they react and release CO2 which fizzes  to get the drug to disintegrate,
dissolve quickly
the CO2 serves as a disintegrator

          ● Insert Tablets –
tablets that are tapered in shape so they can be inserted like a suppository,  Ex vaginal insertion,

         ● Buccal and Sub-lingual Tablets –
need to be relatively small and active ingredients need to be soluble
especially good for drugs that cannot be administered through the GIT ( would be destroyed by stomach
acid or would not be absorbed to blood, or subjected to first pass effect  can avoid this
Buccal  absorption through cheek and oral cavity
Sublingual  absorption into the mucosa layer under the tongue  rich blood vessels
Dissolves within 15 minutes

         ● Chewable Tablets –                         Mannitol
popular with children or anyone who cant swallow
tend to be larger  not intended to be swallowed whole
elminates the concern for disintegration in the GI tract because disintegration( dissolution) occurs in the
chewing process
Mannitol used as a major excipient in chewable tablets because it gives a sweet and cooling sensation
which makes tablet very palatable


         ● Rapidly (Instantly) Disintegrating Tablets:            Lyophilization          Soft Direct
Compression
newest entry into the tablet market
very rapidly dissolving, within 15 seconds  pop in the mouth without any water
medications you need to get into your system quickly or to carry around with you with no access to water
have to be individually wrapped in packets, because a little bit of moisture would dissolve them
manufacturing  lypophilic (freeze drying) and soft direct compression..
ODT

                         (p.2)
The process of manufacturing compressed tablets:

         ● Steel punches and dies (punch & die) as principal components of a tablet press
the lower punch fits into the die and then in the simple machines it just stays there in one position, is
adjusted to a certain height within the die , then the tablet machine works that the upper punch and comes
down and compresses the tablet, and then it is withdrawn and tablet is formed
the lower punch comes up to remove the tablet from the die
the weight of the tablet is determined by the volume of the material that fills the die and the height to where
you adjust the lower punch


          ● Tablet Presses (Tablet Machines)
refer to handout
                  Single Punch Presses
Figure 8.26
Can either be motorized, can be hand presses for small batches, power driven/hand-operated
Feed shoe sweeps the excess powder from the top of the die cavity, then the upper punch comes down and
compresses while lower punch stays in place
As the upper punch comes out, the lower punch pops up to push the tablet out and then the feed shoe
sweeps the tablet out

                     Rotary Tablet Presses
For large batches
More complex
Multi-stationed  they can have 16 or so stations, 16 compressions at once
In the compression process, it’s not just the upper punch putting the pressure, but they both put pressure,
getting compression from both upper and lower end  allows air to escape more easily from the powder
mixture  produces a better tablet
If air is in the tablet, can crumble more easily, more likely in single punch

Necessary properties of the materials to be compressed into tablets:             hopper               machine
feeding mechanism
Bottom line is that the powder has to be in granular form  potassium chloride, etc
For most of the powders and excipients are not in granular form and have to be converted
        ● Free-flow
means free-flowing into the die, and then free-flowing out of the hopper
the hopper is a funnel –looking device., tablet will be fed into automated machine after

         ● Cohesive
they will not compress if not sufficiently cohesive, particularly shipping and handling process
         ● Some lubricant properties
necessary so that they will be ejected easily from the die and so they will not adhere onto the face of the
punches
these lubricant materials are by nature hydrophobic  can foul up bioavailability
Methods for the commercial production (manufacture) of compressed tablets:

        ● The Wet Granulation Method – (the classical method of tablet manufacture)
the method most commonly used

                   Steps:
                   1) Weighing – weigh out all ingredients
                   2) Mixing - the drug, the diluent, and the excipient
these are traditionally mixed in a piece of equipment referred to as a V-Blender
or sometimes may be sifted through a screen to break up any clumps/lumps

                   3) Granulation - solutions of binding agent added to mixture with stirring
have to be very careful here because if you get this mixture too wet, the granules will end up being too hard
tablet preparation is both a science and art

                    4) Screening the damp mass –
                    5) Dry Screening –
traditionally, flat drying pans lined with parchment paper  wet granulation is spread over these drying
trays and placed into oven at low temp with circulation air
fluid-bed drying actually have a device in which you have air at a certain temp and your particles float


                  6) Lubrication –

                  7) Compression

                           (p.3)
          ● The Fluid Bed Granulation (Spray Drying) Method –
alternative way to dry it  more modern way  spray drying is a popular industrial technique
preferred because it could be more easily automated

         ● The Dry Granulation Method of Tablet Compression (“Slugging”) –
               Comminution
Method that is particularly necessary when you’re dealing with drugs that are extremely subject to
hydrolytic degradation  cannot come into contact with moisture)
Also drugs that are heat-labile
Take your drug, diluent and lubricant powders and mix them together and put them through as a
preliminary crude compaction
You make crude tablets, unsuitable tablets using rough machinery  referred to as slugs
Once these are prepared you put them through the process called comminution “reduce particle size” 
mechanical means or mortar and pestle
Put these through a screening process, using a mill or into uniform size
Then you compact and make good tablets

        ● The Direct Compression Method                                            Microcrystalline Cellulose
(Avicel®)
                                                                                   Dicalcium Phosphate

Drug and diluent already in granular form  compress them directly
Avicel is a diluent that is able to be directly compressed without putting into it into any granulation process

        ● Spheronization (Pelletization) Method
modified form of what granulation is

				
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