solid pharmaceutical drug delivery forms: tablets

practical value for appreciating solid dosage forms for pharmacists

- easier overall

- evaluating quality of a generic tablet and capsule when making purchasing decisions

- understand and explain what goes into making tablets and capsule when patients have questions about cost, bioavailability and -equivalence

- for pharmacists who work in industry, know the design of dosage forms and how it would be made to be oral

- identify potential counterfeit generics

why are oral dosad forms still relavent (solid)

- convenient and good for people scared of injectables

- lower cost for actual product and administration, because of independence

- not all drugs can be oral, especially MABs and vaccines

tablets definition

- solid dosage forms with one or more APIs with various diluents/excipients formed by compression or molding

- pills were molded solid dosage forms compounded by pharmacists in the 19th century and compressed in the 20th

- molded limited to ODTs

- the term pill has become colloquially used to mean any solid dosage form

variables influencing tablet behavior

- size

- shape

- weight

- disintegration

-dissolution

- API

- excipient composition

- color

- content uniformity

- weight variation

- coatings

- release mechanism

more compressed tablet

- harder to disintegrate

what can these variables influence

- bioavailability

- adherence

- cost

- reproducibility

- physical and chemical stability

- pharmaceutical elegance and market appeal

- ease of identification

- extent of medication dispensing errors

reasons for popularity of tablet dosage forms

- cost, stability, ease of administration, dosage accuracy, portability, more tamper resistance, embossing/etching

cost

- relatively low large-batch production costs

- well suited for mass production in the pharmaceutical injustry

stability

- solid dosage forms are inherently stable compared to solution or other liquid pharmaceutical dosage forms

- physical, chemical, and microbial

ease of administration

- both tablets and capsules are well suited to easy self-administration which to a large extent accounts for their popularity among patients

dosage accuracy

- assuming they are properly formulated and manufactures with good quality control

- however, there have been major problems with generics produced in China and India for failure to follow cGMPs

portable

- not bulky

- easy to store and ship and travel with

tamper resistance

- more tamper resistant compared to other dosage forms

embossing/etching

- embosing for capsules

- etching for tablets

- to differentiate between different tablets/capsules

compression

- greater force involved in production of compressed tablets, makes tablet susceptible to bioavailability and -equivalence problems

- affects the disintegration, dissolution, and bioavailability of compressed tablets, especially whenever the API is poorly soluble

quality control and assurance

- must be applied at each step

- "in process controls"

- process validation

process validation

- verification that the overall QC process in working

- every batch of tablets made is uniform

- final step of QC

- vital component of manufacturing controls in the pharmaceutical industry

- if incorrect, must send out product recalls

historical evolution of tablet dosage forms

- started off with molding tablets because we didn't have compressing tech in the early 20th century

- now primarily compressed tablets

compressed tablets history

- invented in England in 1878

- helped to promote the development and expansion of pharmaceutical industry by introducing cost-effective mass productions technology

- compresses is a synonym

- tablet manufacture is an industrial process involving compression of powders converted to granulations

specialized and technologically advanced tablets

- sublingual

- transmucosal

- ER or repeated-action

- ODTs

- 3D printing tablets

why made specialized tablets

- for onset of action

- specific drug delivery

- rapid absorption for transmucosal

- rapid dissolution for ODT

- preference and specific API and if it works with the style

shapes and sizes of tablets

- grooved/ scored

- discoid

- thickness/height

thickness

- should not be >5% or else automated counting machines in pharmacies will malfunction

- if pressure exerted by punches during compression process, then thickness will not be uniform

punch and die set

- consists of an upper punch, a lower punch, and a die cavity

- the tablet granulation is then compressed by the force applied by the upper and lower punches

considerations for compressed tablets

- complexity, API %, shape and dimensions of punches and dies

complexity of tablet

- complex industrial process

- rarely a function of compounding pharmacies

- quality and uniformity depend on variables

API % in tablets

- higher API ratio is harder to formulate

- diluents are added with purpose to make the tablet more compressible

shape and dimensions of the punches and dies

- determine shape and dimensions and weight of tablets

coating and taste masking

- sugar coating

- film coating

- imprinting is made on the surface of the coated tablets after the coating process has been completed

- embossing/engraving consists of etching on the face of the punches that compress the tablets, which is done by upper and lower punches

sugar coating

- older form

- mask tastes and allows for easier identification of tablet

- may even help hold the tablet physically

- adds to the dimension (size) and weight of the tablets

film coating

- newer and preferred method of coating'

- uses polymeric materials that apply a thin coating to the tablet and do not substantially increase size or weight of tablet

- does not cover any etchings on tablet

purpose of coating

- masking the taste/odor of APIs or excipients

- enhance chemical stability of API by excluding moisture

- coating prevents powder shedding/chipping

- ease of administration

- ease of identification

unblinding clinical trials with taste

- RCT or oral typhoid vaccine vs placebo

- taste and aroma was distinct for the experimental vaccine

- oral zinc vs calcium of the patients randomized to the experimental zinc treatment noted the telltale metallic aftertaste of zinc

- patients knew that they were taking the active or placebo

multilayer compressed tablets

- press-coated

- layered

press-coated tablets

- a tablet within a tablet; maybe because APIs aren't compatible or if they have different release times

- outer layer usually intended for immediate release

- inner core is for extended or delayed release

layered tablet

- 2 separate leavers give a unique characteristic appearance and identity to the tablet

- also a way to handle chemically incompatible APIs

- one layer could be for immediate release and other for controlled

controlled release tablet types

- delayed

- enteric coated

- ER/Extended length

- solid dosage forms are very popular and useful that can be either tablets or capsules

delayed release

- also called repeat action

- provide 2 separate doses, one immediately and other dose later

enteric coated

- formulated to not release API in the stomach, but in the less acidic environment of the small intestine where most drug absorption occurrs

- this could be for reasons of chemical stability of the API or to avoid gastric irritation

extended release or extended length

- sustained release

- gradual release of API over 6/8/12/24 hour period

- currently the most popular form of controlled release dosage forms

- API coated with different types or amounts of polymers to provide this gradual release

dose dumping

- when you crush controlled/delayed release

- example is oxycontin: designed to give oxycodone over prolonged period of time

- when crushed, there is a rapid release in plasma concentration

effervescent tablets

- Alka seltzer

- effervescent Tablets - NaHCO3 + Citric (or

Tartaric) Acid --> CO2

- reaction has therapeutic purpose and the CO2 acts as a disintegrator

- the chemical reaction occurs when tablet comes in contact with water

insert tablets

- tapered at one or both ends like a suppository

- vagina inserts in example

buccal or sublingual tablets

- not all API can do this because drugs are specifically designed in a way to be absorbed in check or under the tongue; NOT SWALLOWED

- no GI route and avoid first pass effect

- not appropriate for large API because the tablets themselves are small

- API should be soluble

- provides rapid onset of action

- ideal for drugs that may be destroyed in gastric contents/poorly absorbed in gut

chewable tablets

- base of mannitol or sorbitol

- or children or other patients with difficulty swallowing

- water not required

- not intended to be swallowed whole and must be chewed to bypass disintegration step

- ODTs are variation of chewable tablet

- Mylanta, Maalox, and Tums are inorganic chewable antacids

orally disintegrating tablets

- a way for pharma to extend patent

- newest types of specialized tablets introduced in mid to late 1980s

- unlike SL or bucc, ODTs are intended to be swallowed after dissolution and DON'T pass bypass first pass metabolism

rapidly disintegrating tablets

- 500 mg maximum weight, most are smaller

- disintegration in the mouth must be within 30 seconds

advantages of RDTs

- patient compliance is greater, especially for psych patients who try and spit tablets out

- don't need water to take

- mitigating the effects of patent expirations

importance of taste and mouth feel for ODTs

- related to palatability, and important consideration for patient acceptance and adherence

- flavoring and sweetening agents may be incorporated into the formulation

ODT formulation and manufacturing technologies

- modified-sugar systems are most commonly used

- lyophilized systems to make wafers

- floss systems to make something like cotton candy

stainless steel punch and dies system

- allows for mass production of tablets

- circular and rotates around

- lower punch fits into the dies cavity, and serves as the floor/platform for the granulated powder that is introduced to the die cavity

- upper punch then comes down into the die cavity with pressure to compress the granulated powder into a tablet

table press/single punch tablet press

- less common; in compounding pharmacies

- one at a time

rotary press

- smaller batched of tablets

- found in compounding pharmacies

- can also be very large and may sometimes be used in industry

- goes straight through like assemble line

- the lower punch rises simultaneously with the entrance of upper punch into the die cavity, so that pressure is applied from both the upper and lower directions, resulting in compaction of the granules into a tablet

key properties of materials to be compressed into tablets

- free flow

- cohesive

- some lubricant properties

free flow

- ensures uniform fill from "hopper" and machine feeding mechanism

- having tablet formulation in granulated form ensures fere flow

hopper

- a funnel-shaped component of the tablet machine

- holds the granulated formulation ingredients and feeds the granulation into the die cavity during the compression cycle

cohesive

- necessary so that tablets will hold together and not fall apart during shipping and handling

lubricant

- to prevent adhesion or sticking to the walls of the die or faces of tablet punches during the compression cycle

- allow the finished tablet to be freely ejected from the die cavity once the compression cycle is completed

wet granulation method

- ungranulated powdered don't flow freely, so they must be converted to granular form

- modern high-speed/high-capacity tablet presses require the materials for compacting to be free-flowing

wet granulation step 1

- weighing

- accurately weigh each ingredient in the tablet formulations

wet granulation step 2

- mixing/blending using appropriate devices

- double conical blender (V-blender) is a popular example

- complete mixing is essential to achieving a homogenous blend of powders which will ensure content uniformity and accurate doses of the finished tablets

wet granulation step 3

- granulation

- solutions of binding agent added to mixture with stirring

- referred to as forming the wet granulation

- controlled volumes of liquid solvent are added to the powdered formulation to form a damp mass.

too much solvent

- the granules will be too hard after drying

too little solvent

- resultant granules will crumble and will not compress

wet granulation step 4

- screening the damp mass

- the damp mass is forced through a 6 or 8 mesh screen by hand or mechanical granulator to form the granules

wet granulation step 5

- dry screening

- moist granules that were formed in step 4, are spread out on large sheets of parchment paper on drying trays, and then the trays are placed in drying ovens with circulating air to facilitate uniform drying

wet granulation step 6

- lubrication

- a lubricant powder is forced through a screen and sprinkled over the final dried granulation

- this is to ensure free flowing of the granules in the tablet press during compression cycle

wet granulation step 7

- compression with high speed rotary machines in the industry

fluid bed granulation: spray-drning method

- widely used industrial modification of the traditional wet granulation method

- more automated and required more equipment

- faster

- more uniform drying

- technique also used for the film coating of tablets

dry granulation step 1

- slugging

- API+ diluent are mixed and put through preliminary compaction with heavy duty compacting device

- produces slugs that are poorly or roughly compacted forms of powder because they aren't compacted well

dry granulation step 2

- slugs are comminuted by screening or milling

dry granulation step 3

- screened slugs compacted in a standard rotary or single punch tablet press

direct compression diluents

- microcrystalline cellulose

- dicalcium phosphate

direct compression method

- one more alternative to the traditional wet granulation method of tablet production

- also suitable for APIs that are sensitive to moisture or heat

- these materials are naturally crystalline: granular like common table salt

- if wither of these diluents make up the majority of the weight of the tablet, and the API is a much smaller constituent, the formulation can be compressed

- this method will not be suitable for large API proportion

appearance of tablets

- smooth and shiny surface preferred

- achieved with coating

- chipping/cracking

- shedding

- mottling

- thickness must be uniform

tablet hardness or tablet friability

- refers to the ease or tendency for chipping, abrasion, breaking

- too hard is inadequate disintegration/dissolution

- occur when the tablets do not have sufficient hardness

tablet disintegration

- governed by USP tablet disintegration test

- measures the time required for the tablet to break apart into smaller fragments

- the test utilizes various devices that dip the tablets into stimulated gastric fluid at controlled temperature, and agitation resembling the peristaltic motion of the GI tract

tablet dissolution

- the rate of dissolving API

- USP sets limits for tablet dissolution tests

- device is somewhat similar to the tablet disintegration tester, but it is necessary to analyze the rate at which the API goes into solution in simulated GI fluid

- a QC test to detect problems that affect bioavailability

content and weight uniformity of tablet

- 5% within each other for weight variation and content uniformity

3 causes that cause the lack of proper content uniformity

- granulation too soft or too hard

- inadequate blending

- poor choice of excipients

tablet excipients affect:

- content uniformity

- friability

- disintegration

- dissolution

- bioavailability

excipients differ between

- brand and generics

diluents

- also called fillers

- lactose, calcium salts, microcrystalline cellulose, hydroxypropyl methylcellulose, kaolin, mannitol, sorbitol, sucrose, inositol

- main function is to add bulk to tablets with low dose of API

requirements for fillers

- to be compatible with the API

- to not adversely affect the granulation process

binders

- granulators

- starch, gelatin, cellulosics, polyvinylpyrrolidone

(PVP), sucrose, lactose, glucose, molasses, acacia, sodium alginate,

carboxymethylcellulose (CMC), ethylcellulose, Polyethylene glycol (PEG), Veegum®, water, alcohol, waxes

- necessary to form the granulation to provide the necessary cohesiveness which is necessary for the compaction to occur

- starch, when added as a wet slurry, acts as a binder

- starch acts as disintegrator when added dry

lubricant as additive

- magnesium stearate, calcium stearate, stearic acid, PEG

- hydrophobic materials a lubricant effect to ensure that the granulation will be free-

flowing during the compression cycle. The amount of lubricant used is critical, because if too much, it will interfere with disintegration and dissolution due to the hydrophobic effect. PEG is appropriate for tablets that need to be water soluble

purpose of lubricants

- prevent adhesion of the granulation to the surface of the die and punch faces during compression

- improve flow properties of the granulation during the compression cycle

- facilitate tablet ejection from the die cavity

- reduces the amount of pressure that the punch must apply to compress the tablet, which may obviate bioavailability problems

- promotes uniform tablet density and also obviate bioavailability problems

glidants

- another term for lubricants

- colloidal silicon dioxide

disintegrants

- corn starch, potato starch, salts of alginic acid (alginates), gums, cross-liked polymers like PVP, Veegum®, methylcellulose, CMC. agar, bentonite, guar gum, sodium starch glycolate, sodium bicarbonate + tartaric or citric acid

- to promote tablet disintegration

- some of these also used as binders depending on their forms and the functions they serve

coloring agents

- dye migration inhibitors: tragacanth, attapulgite, acacia, color "lakes"

- FDA approved dyes are used to impart color to tablets

- provide a distinct tablet identity

- to distinguish among multiple strength, like warfarin or levothyroxine

- to prevent and detect counterfeit tablets, because colors in tablets are hard to duplicate

color lakes

- refers to a dye that has been adsorbed onto an insoluble metallic oxide (like Zinc Oxide or Magnesium Oxide)

- reducing Mottling problems

flavoring agents

- mostly limited to chewable tablets or ODTs

capping

- convex space on tablet slices off

splitting

- occurs with grooved/scored tablets and occurs with powder shedding

reasons for capping/splitting

- excessive fines: free ungranulated powder in tablet granulation

- entrapped air in the final tablet: more with single punch

- excessive force of compaction

tablet weight and tablet weight variayiontess

- USP

- involves taking 20 tablets from batch and must be within +- 10% of each other to pass

- applicable to uncoated or film coated tablets only, NOT sugar coated

tablet hardness and friability test

- friabilator drum spins tablets around and sees in the tablets break apart

- must stay in tact to pass

- hardness test involved placing the tablet in a device resembling pair of pliers, where you squeeze it and the device measures the pressure it takes to break the tablet

QC tests for tablets

- content uniformity tests: +- 5% of FILM COATED and SUGAR-COATED tablets

- tablet disintegration tests: measure time required for the tablets to break apart and fall through screen; NOT applicable to controlled release tabs or capsules

- tablet dissolution tests: measure % API that goes into solution under controlled conditions in 30 minutes

- all USP regulation

requirements for packing and storing ctablets

- USP requires tight closures and light resistant containers for many tablets and capsules, so most solid dosage forms are dispensed in amber colored containers

- desiccant is often included for moisture sensitive APIs and desiccant should not be discarded from original container

other oral dosage forms

- lozenges (troches)

- lollipops/ transmucosal delivery device

- some compounding pharmacies make these for children and molds are available for such compounding