Evalution test for tablets

Evalution test for tablets


 

Introduction

The quantitative evaluation and assessment of a tablet's chemical, physical and bioavailability properties are important in the design of tablets and to monitor product quality. These properties are important since chemical breakdown or interactions between tablet components may alter the physical tablet properties, and greatly affect the bioavailability of the tablet system. There are various standards that have been set in the various pharmacopoeias regarding the quality of pharmaceutical tablets. These include the diameter, size, shape, thickness, weight, hardness, disintegration and dissolution characters. The diameters and shape depends on the die and punches selected for the compression of tablets. The remaining specifications assure that tablets do not vary from one production lot to another. The following standards or quality control tests should be carried out on compressed tablets1.

General appearance

The general appearance of tablets, its visual identity and overall 'elegance' is essential for consumer acceptance, control of lot-to-lot uniformity and general tablet-to-tablet uniformity and for monitoring the production process. The control of general appearance involves measurement of attributes such as a tablet's size, shape, color, presence or absence of odour, taste, surface textures, physical flaws and consistency

Size and shape

The shape and dimensions of compressed tablets are determined by the type of tooling during the compression process. At a constant compressive load, tablets thickness varies with changes in die fill, particle size distribution and packing of the powder mix being compressed and with tablet weight, while with a constant die fill, thickness varies with variation in compressive load. Tablet thickness is consistent from batch to batch or within a batch only if the tablet granulation or powder blend is adequately consistent in particle size and particle size distribution, if the punch tooling is of consistent length, and if the tablet press is clean and in good working condition.

The thickness of individual tablets may be measured with a micrometer, which permits accurate measurements and provides information of the variation between tablets. Tablet thickness should be controlled within a +_5% variation of a standard value. Any variation in thickness within a particular lot of tablets or between manufacturer's lots should not be apparent to the unaided eye for consumer acceptance of the product. In addition, thickness must be controlled to facilitate packaging.

The physical dimensions of the tablet along with the density of the material in the tablet formulation and their proportions, determine the weight of the tablet. The size and shape of the tablet can also influence the choice of tablet machine to use, the best particle size for granulation, production lot size that can be made, the best type of tableting processing that can be used, packaging operations, and the cost of production.

The USP has provided limits for the average weight of uncoated compressed tablets. These are applicable when the tablet contains 50mg or more of the drug substance or when the latter comprises 50% or more, by weight of the dosage form. Twenty tablets are weighed individually and the average weight is calculated. The individual tablet weights are then compared to the average weight. Not more than two of the tablets must differ from the average weight by not more than the percentages stated in Table 1. No tablet must differ by more than double the relevant percentage. Tablets that are coated are exempted from these requirements but must conform to the test for content uniformity if applicable

Average weight
Percent dif ference

130mg or less         10

More than 130mg through 324mg         7.5

More than 324mg                       5


 

Organoleptic properties

Color is a vital means of identification for many pharmaceutical tablets and is also usually important for consumer acceptance. The color of the product must be uniform within a single tablet, from tablet to tablet and from lot to lot. Non uniformity of coloring not only lack esthetic appeal but could be associated by the consumer with non-uniformity of content and general poor product quality. Non uniformity of coloring is usually referred to as mottling. The eye cannot differentiate small differences in color nor can it precisely define color and efforts have been made to quantitate color evaluations. Reflectance spectrophotometry, tristimulus colorimetric measurements and micro reflectance photometer have been used to measure color uniformity and gloss on a tablet surface ².

Odor may also be important for consumer acceptance of tablets and can provide an indication of the quality of tablets as the presence of an odor in a batch of tablets could indicate a stability problem, such as the characteristic odor of acetic acid in degrading aspirin tablets. However, the presence of an odor may be characteristic of the drug (e.g. vitamins), added ingredients (e.g. flavoring agent) or the dosage form (e.g. film-coated tablets).

Taste is also important for consumer acceptance of certain tablets (e.g. chewable tablets) and many companies utilize taste panels to judge the preference of different flavors and flavor levels in the development of a product. Taste preference is however subjective and the control of taste in the production of chewable tablets is usually based on the presence or absence of a specified taste.

Content uniformity

The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch. Due to increased awareness of physiological availability, the content uniformity test has been included in the monographs of all coated and uncoated tablets and all capsules intended for oral administration where the range of size of the dosage form available include 50mg or smaller sizes. Tablet monographs with a content uniformity requirement do not have weight variation requirements4. For content uniformity test, representative samples of 30tablets are selected and 10 are assayed individually. At least 9 must assay within ±15% of the declared potency and none may exceed ± 25%

Mechanical strength of tablets

The mechanical strength of a tablet provides a measure of the bonding potential of the material concerned and this information is useful in the selection of excipients. An excessively strong bond may prevent rapid disintegration and subsequent dissolution of a drug. Weak bonding characteristics may limit the selection and/or proportion of excipients, such as lubricants, that would be added to the formulation.

The mechanical properties of pharmaceutical tablets are quantifiable by the friability5, hardness or crushing strength6-8, crushing strength-friability values7-8, tensile strength9-11 and brittle fracture

Friability

Friction and shock are the forces that most often cause tablets to chip, cap or break. The friability test is closely related to tablet hardness and is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up3. Normally, when capping occurs, friability values are not calculated. A thick tablet may have less tendency to cap whereas thin tablets of large diameter often show extensive capping, thus indicating that tablets with greater thickness have reduced internal stress2.

Hardness or Crushing strength

The resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The small and portable hardness tester was manufactured and introduced by Monsanto in the Mid 1930s. It is now designated as either the Monsanto or Stokes hardness tester. The instrument measures the force required to break the tablet when the force generated by a coil spring is applied diametrally to the tablet. The Strong-Cobb Pfizer and Schleuniger apparatus which were later introduced measures the diametrically applied force required to break the tablet.

Hardness, which is now more appropriately called crushing strength determinations are made during tablet production and are used to determine the need for pressure adjustment on tablet machine. If the tablet is too hard, it may not disintegrate in the required period of time to meet the dissolution specifications; if it is too soft, it may not be able to withstand the handling during subsequent processing such as coating or packaging and shipping operations. The force required to break the tablet is measured in kilograms and a crushing strength of 4Kg is usually considered to be the minimum for satisfactory tablets2. Oral tablets normally have a hardness of 4 to 10kg; however, hypodermic and chewable tablets are usually much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).Tablet hardness have been associated with other tablet properties such as density and porosity. Hardness generally increase with normal storage of tablets and depends on the shape, chemical properties, binding agent and pressure applied during compression7,8.

Another measure of the mechanical strength of pharmaceutical tablets that have been used is the crushing strength-friability ratio (CSFR)7,8. The CS provides a measure of tablet strength while F is a measure of tablet weakness. Studies have shown that the higher the CSFR values, the stronger the tablet7,8.

Tensile strength

A non-compendial method of measuring the mechanical strength of tablets that is now widely used is the tensile strength. This is the force required to break a tablet in a diametral compression test. The radial tensile strength, T, of the tablets can be calculated from the equation:

T = 2 F / π d H (1)

where F is the load needed to break the tablet, and d and H are the diameter and thickness respectively. Several precautions must be taken when using the equation. Various factors e.g. test conditions, deformation properties of the material, adhesion conditions between compact and its support and tablet shape may influence the measurements of the tensile strength ⁶.

Some authors have suggested the determination of axial tensile strength because of the sensitivity of the radial tensile strength measurements to crack propagation variations13-14. The axial tensile strength (Tx) can be calculated from the following relationship:

Tx = 4 F / π d2 (2)

Tensile strength has been used in combination with indentation hardness to evaluate tabletting performance of materials¹². The indentation hardness is a time-dependent property used to measure the plastic yield of a material. It can be determined by either static methods (e.g. the Brinell, Vickers and Rockwell hardness tests) or the dynamic methods15. The static indentation methods involve the formation of a permanent indentation on the surface of the material tested and the hardness is determined by means of the load applied and the size of the indentation formed16. In the dynamic indentation tests, either a pendulum is allowed to strike from a known distance or an indenter is allowed to fall under gravity unto the surface of the test material. The hardness is then determined from the rebound height of the pendulum or the volume of the resulting indentation. Using an apparatus consisting of a steel sphere pendulum acting as an indenter, Hiestand et al.12 estimated the hardness (i. e. the mean deformation pressure) of compacted materials by dividing the energy consumed during the impact by the volume of indentation.

Brittle fracture index (BFI)

Hiestand et al.17-18 have studied the effects of decompression on the tabletting performance of pharmaceutical materials and stated that whether or not fracture occurs during the shear deformation which accompanies decompression depends on the ability of the materials to relieve stresses by plastic deformation without undergoing brittle fracture and this ability is a time-dependent phenomenon. Those materials that relieve stress rapidly are less likely to cap or laminate. The brittleness test is based on the Griffith fracture theory which teaches that, for crack growth to occur, the energy stored at the tip of a crack must just exceed the energy required to form two new surfaces resulting from the propagation of the crack. Also, the amount of energy stored at the tip of a crack is a function of the dimensions of the crack.

In the light of this theory, Hiestand et al.17 showed that when compacts are made with a small axially-oriented round hole at their centre, the compact is nearly always weakened. Under the conditions of the tensile strength test, elasticity theory predicts that the stress concentration factor for the hole should be about 3.0. Hiestand18 showed that for isotropic materials, the ratio of compressive stress at the centre of a compact to the tensile stress, which causes fracture, has a value of 3.7. However, recent studies have shown that for a ratio of hole diameter to disc of about 0.1, the stress concentration factor, i.e. the ratio between tensile stress at the inner boundary of the hole and the tensile stress of a tablet having no hole, should be around 1019,20. Thus, the BFI is obtained by comparing the tensile strength of tablets with a hole at their centre, which acts as a built-in stress concentration defect, with the tensile strength of tablets without a hole, both at the same relative density18,21. The brittle fracture index (BFI) of the tablets was calculated using the following equation

BFI = [(T / To) – 1 (3)

Where T is the tensile strength of the tablet without a hole and To, to the tensile strength of a tablet with a hole. The theoretical value of BFI range is 0 - 1 when the stress concentration factor is 3. Since the BFI is an inverse measure of localized stress relief, it should indicate the tendency of a tablet to laminate or cap. In principle, BFI values in excess of unity may occur. In practice, however, one probably cannot make an intact tablet of a material with a BFI of 1. Therefore, the observed range of values may not exceed the 0 - 1 range. Where by the closer the value of BFI to 0, the less stress relief takes place. A high value of BFI is an indication of the tendency of the tablet to laminate during the compaction process. A low BFI value is desirable for minimal lamination and capping during production^9,21.

Robert and Rowe ²² extended the determination of the BFI to compact of 'tablet-sized' dimensions. This allows the BFI to be measured at strain rates and conditions approaching those normally used in tabletting. They found the BFI values for microcrystalline cellulose, tablettose and heavy magnesium carbonate to be in good agreement with the results of previous workers12, 17 . Itiola & Pilpel21 using both granular and powdered metronidazole formulations studied the mechanical properties of the tablets and differentiated between the bond strength of the tablets as measured by their tensile strength and the tendency of the tablets to laminate or cap as measured by the brittle fracture index values. They found that tablets made from granules had lower tensile strength than those made from powders but were also less brittle.

The BFI have also been used to characterize the mechanical properties of pharmaceutical formulations9,^23-25 and some local starches, namely cassava, potato and yam starches^23,24. Tablets of these starches were shown to possess low tensile strength values, but also had low BFI values. Studies have also shown that the BFI is affected by the nature and concentration of binding agent, compression pressure and compression speed. Generally, the higher the BFI values, the more friable a tablet is likely to be

Disintegration

For a drug to be absorbed from a solid dosage form after oral administration, it must first be in solution, and the first important step toward this condition is usually the break-up of the tablet; a process known as disintegration²⁶. The disintegration test is a measure of the time required under a given set of conditions for a group of tablets to disintegrate into particles which will pass through a 10 mesh screen. Generally, the test is useful as a quality assurance tool for conventional dosage forms.

The disintegration test is carried out using the disintegration tester which consists of a basket rack holding 6 plastic tubes, open at the top and bottom, the bottom of the tube is covered by a 10-mesh screen. The basket is immersed in a bath of suitable liquid held at 37^oC, preferably in a 1L beaker. For compressed uncoated tablets, the testing fluid is usually water at 37^oC but some monographs direct that simulated gastric fluid be used. If one or two tablets fail to disintegrate, the test is repeated using 12 tablets. For most uncoated tablets, the BP requires that the tablets disintegrate in 15minutes (although it varies for some uncoated tablets) while for coated tablets, up to 2hours may be required³. The individual drug monographs specify the time disintegration must occur to meet the Pharmacopoeial standards.

In the past, the only release index required for a tablet was its disintegration time which does not necessarily measure the physiological availability of the drug in a patient. Studies have shown that the agitation of the gastric contents during normal contractions is quite mild in contrast to the turbulent agitation produced in the disintegration test apparaus²⁷. The low order magnitude of agitation in the stomach produces substantially higher disintegration in vivo than those obtained using the USP apparatus. Furthermore, the particles of the disintegrated tablets are not dispersed throughout the stomach but remains as an aggregate. Thus, the tablet disintegration test is limited to manufacturing control of lot-to-lot variations in individual products and is not a measure of bioavailability²⁷. Nevertheless, it is used to provide a simple and useful means for monitoring and controlling the quality of tablets.

Theories of disintegration

Several mechanisms of tablet disintegration have been proposed. Some of these are given below. Even though these concepts are listed separately, inter-relationships probably occur in almost all tablet formulations.

Evolution of gas

If a gas is evolved by a chemical reaction when the tablet comes into contact with water, then the tablet will disintegrate. This is the basis for the manufacture of effervescent tablets. An example of such a reaction is of sodium bicarbonate with citric and tartaric acids, which yields carbon dioxide. Peroxides incorporated in certain formulations decompose in the presence of oxygen and this also causes disintegration.

Heat of wetting

The heat produced when a tablet is immersed in water causes the entrapped air in the tablet to expand and exert sufficient pressure to disintegrate the tablet.

Effect of water absorption

The water absorbed by the tablet initiate disintegration, but this depends on the solubility of the drug and other ingredients present.

Swelling

The grains of the disintegrant, particularly of starches, swell in the presence of water and exert pressure on the granules to force them apart. Shangraw et al reported that tablets of water insoluble drugs disintegrated faster with starches than those of water soluble drugs due to the diminished water absorption capacity of the starches in the latter case.

Porosity of tablets

It has been shown that penetration of water into a tablet is proportional to its mean pore diameter or porosity. The porosity and permeability of tablets decrease as the tabletting pressure is increased, and as the porosity decreases, the disintegration time increases. Though no quantitative relationships have been reported between disintegration and penetration times, generally short disintegration times are associated with rapid fluid penetration.

Dissolution

Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.

Dissolution is considered one of the most important quality control tests performed on pharmaceutical dosage forms and is now developing into a tool for predicting bioavailability, and in some cases, replacing clinical studies to determine bioequivalence. Dissolution behaviour of drugs has a significant effect on their pharmacological activity. In fact, a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been demonstrated and is generally referred to as in vitro-in vivo correlation, IVIVC^..

Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid following oral administration depending on their design 

Dissolution kinetics is important in determining the bioavailability of a drug39. Levy45 and some other workers46 reported that the dissolution rate controls the rate of build up of certain drugs in the blood stream. It was thus recognised that in-vitro dissolution kinetics provides useful information on the availability of drugs and their subsequent therapeutic effects in-vivo45. This led to the inclusion of dissolution tests in the United States NF XIII (1970) and USP XVIII (1970) monographs for one capsule and twelve tablet preparations. In 1975, dissolution tests were included in the British Pharmacopoeia (amendment to BP 1973) for digoxin tablets. The various pharmacopoeias contain specifications on the dissolution requirements of various drugs. A variety of designs of apparatus for dissolution testing have been proposed and tested, varying from simple beaker with stirrer to complex systems with lipid phases and lipid barrier where an attempt is made to mimic the biological milieu. The choice of the apparatus to be used depends largely on the physicochemical properties of the dosage form

Theories of dissolution

Some workers  have reviewed the factors which can affect the dissolution of tablets and these include the stirring speed, temperature, viscosity, pH, composition of the dissolution medium and the presence or absence of wetting agents.

Physical models have been set up to account for the observed dissolution of tablets. According to Higuchi50, there are three models which either alone or in combination, can be used to describe the dissolution mechanisms. These are:

The Diffusion layer model

This model (Fig 2) assumes that a layer of liquid, H cm thick, adjacent to the solid surface remains stagnant as the bulk liquid passes over the surface with a certain velocity. The reaction at the solid/liquid interface is assumed to be instantaneous forming a saturated solution, Cs, of the solid in the static liquid film. The rate of dissolution is governed entirely by the diffusion of the solid molecules from the static liquid film to the bulk liquid according to Fick's first law:

J = - Df dc / dx (4)

where J is the amount of substance passing perpendicularly through a unit surface area per time, Df ,is the diffusion coefficient and dc / dx, is the concentration gradient. After a time t, the concentration between the limit of the static liquid layer and the bulk liquid becomes Ct. Once the solid molecules pass into the bulk liquid, it is assumed that there is rapid mixing and the concentration gradient disappears.

The theory predicts that if the concentration gradient is always constant i. e. Cs - Ct is constant because Cs >> Ct ("sink" conditions which usually mean Cs > 10 Ct) then a uniform rate of dissolution is obtained.

 

The Interfacial Barrier Model

In the interfacial barrier model (Fig 3), it is assumed that the reaction at the solid/liquid interface is not instantaneous due to a high activation free energy barrier which has to be surmounted before the solid can dissolve. Thereafter the dissolution mechanism is essentially the same as in (i) above, with the concentration at the limit of the static layer of liquid becoming Ct after time t.

The rate of diffusion in the static layer is relatively fast in comparison with the surmounting of the energy barrier, which therefore becomes rate limiting in the dissolution process.

Fig. 3. Diagrammatic representation of the free energy barrier to dissolution

The Danckwert's Model

The Danckwert's model (Fig 4) assumes that macroscopic packets of solvent reach the solid/liquid interface by eddy diffusion in some random fashion.

 
At the interface, the packet is able to absorb solute according to the laws of diffusion and is then replaced by a new packet of solvent. This surface renewal process is related to the solute transport rate and hence to the dissolution rate.


The rate laws predicted by the different mechanisms both alone and in combination, have been discussed by Higuchi. However, the earliest equation expressing dissolution rate in a quantitative manner was proposed by Noyes and Whitney as:-

dc / dt = k (Cs - Ct) (5)

where dc / dt is the rate of change in concentration with respect to time, and k is the rate constant. The integrated form of the equation is:

In [Cs / (Cs - Ct) ] = kt (6)

The equation in resemblance to the other rate law equations, predicts a first order dependence on the concentration gradient (i.e. Cs - Ct ) between the static liquid layer next to the solid surface and the bulk liquid. Noyes and Whitney explained their dissolution data using a concept similar to that used for the diffusion model. This considerations relate to conditions in which there is no change in the shape of the solid during the dissolution process ( i. e. the surface area remains constant). However, for pharmaceutical tablets, disintegration occurs during the dissolution process and the surface area generated therefore varies with time.

Aguiar et al proposed a scheme which holds that dissolution occurs only when the drug is in small particles. Wagner modified this idea and showed that dissolution occurs from both the intact tablet and the aggregates and/or granules produced after disintegration by using a plot of the percentage of drug dissolved versus time on logarithmic - probability graph papers.

A modification of this approach was proposed by Kitazawa et al. Employing the integrated form of Noyes and Whitney equation (equation 6), they determined the dissolution rate constant of uncoated caffeine tablets. The Kitazawa equations have been used to determine the dissolution rates of some pharmaceutical tablet formulations

Routes of Drug Administration

Routes of Drug Administration (Enteral, Parenteral, Topical)

                    I.                        Enteral Routes: Placement of drug directly into any part of the GIT is called an 'enteral' mode of administration

a)                  Oral: Swallowing a drug through mouth

  
 

        Advantages:

•   Most commonly used method as it is safe, convenient & painless procedure
  
•  Economical as sterilization of drug products is not essential
  
•  No need of any assistant
  

      Disadvantages:

•   Onset of action is slower 
  
•   Polar drugs can't be given as they are not absorbed (eg: Streptomycin) 
  
•   Drugs are destroyed by the digestive juices (Eg: Penicillin-G, Insulin, Oxytocin)
  
•  1^st pass effect (those destroyed in liver before reaching systemic circulation) (eg: Morphine, Isoprenaline) 
  
•     Bad test & Bad smell & irritant drugs can't be given 
  
•   Drugs can't be given to unconscious & uncooperative patients
  
• Drugs can't be given during emesis
  

b)                Sublingual / Buccal


The drug is place beneath the tongue (sublingual) or crushed in mouth and spread over the buccal mucosa (Buccal).

Advantages:

• Quick onset of action because of rapid absorption due to more blood supply in that region
  
• 
  Bypasses the portal circulation
  
• no 1^st pass metabolism
  
• 
  Drug action can be terminated at any time when side effects are observed
  

  Disadvantages:
  

• Distasteful, irritant drugs can't be given
  
• Higher molecular weight drugs can't be absorbed (eg; insulin)
  

  Examples
  

  Isosorbide dinitrate tablets & Nitroglycerin tablets (for Angina), Isopranline  sulfate tablets (for Bronchial Asthma), Nifedipine in powder form (in Hypertension)
  

  
   

c)                  Rectal: Through Rectum  (Suppositories, Enema)

Advantages:

    Useful in patients with nausea and vomiting

    1^st pass metabolism is greatly bypassed as a major portion of the drg is absorbed from external haemorrhoidal veins

    Useful for gastric irritant drugs

Disadvantages:

    Chances of rectal inflammation

    Absorption is irregular

    Inconvenient and embarrassing to the patient

Examples

    Dulcolax & Glycerine suppositories, enemas, ointments for Local action

    Aminophylline (Bronchodillator) & Indomethacin (Anti-inflammatory agent) Suppositories for Systemic action

 

                  II.   Parenteral Routes:
Routes other than "Enteral" are called 'Parenteral' routes of administration. Administration of drugs by injection, by topical application to skin or by inhalation through the lungs are all parenteral.

a)                  Intravenous:Through lumen of the veins

 

Advantages:

    Directly enters into the systemic circulation & no 1^st pass effect & quicker onset of action

    Less dose is needed to achieve greater therapeutic effects

    Valuable in emergency

    Can be given evening unconscious, uncooperative patients those are having nausea, vomiting & diarrhea

    Hypertonic solutions & GIT irritant drugs can be infused

    Large volume of fluids can be infused at a uniform rate

    Amount of the drug can be controlled with an accuracy

Disadvantages:

    Strict aseptic conditions are needed

    Patient has to depend upon other person for administration of drug

    Painful

    Risky because once the is injected it can't be recalled

    Introduction of any air or particulate matter produce embolism which is fatal

    Drugs in suspensions & Oily drugs can't be given

    Depot injections can's be given

    Venous thrombosis & Thrombophlebitis of the vein injected

    Necrosis around the site of action

Examples: Glucose, Glucose normal saline, Dopamine & Norepinephrine drips

 

b)                 Intramuscular

    Deltoid muscle or gluteal mass of left or right buttock

    Vastus muscle underlying the lateral surface of the thigh

Advantages:

    Absorption is more predictable, less variable & rapid compared to Oral route

    Depot injections can be given

Disadvantages:

    Perfect aseptic conditions are needed

    Chances of abscess at the site of injection

    Chances of nerve damage leading to paresis of muscle supplied by it

    Large volumes can't be given (maximum 5 – 10 ml)

 

Examples: Depot injection of Testosterone, Antibiotics, Antiemetics

 

c)                 Intraperitoneal

 

    Into the peritoneal space

    Rapid absorption due to large surface area

    Painful, risky

    Antirabies injection can be given

d)                Intrathecal (Intraspinal)

 

    Into the subarachnoid space

    They crosses BBB & Blood CSF barrier

    Strict aseptic conditions & grater expertise is needed

    Its painful & risky procedure

    Many radiopaque contrast media for myelography (to visualize spinal cord) are given through this route

    Xylocaine injection for providing Spinal Anesthesia

 

e)                  Intramedullary:
Injection into the tibial or sternal bone marrow

f)                   Intra-arterial:
into the lumen of the desired artery

g)                  Intra-articular: injection directly into the joint space

h)                 Subcutaneous: Injection into the subcutaneous tissue under the skin

Inhalation: Inspiration through nose or mouth

 

III.                        Topical Routes

a)                 Transdermal

    Transdermal Patches

    In these adhesive patches, the drug is incorporated into a polymer (usually Polyisobutylene) which in turn is bonded to an adhesive plaster

    The drug is delivered at the skin surface by diffusion, for percutaneous absorption into circulation

    These preparations are designed to provide steady & smooth plasma concentration of the drug for a period ranging from 1-3 days from the site of their application

    Site of application: Chest, Abdomen, Upper arm or Mastoid region

    Examples: Transdermal Patches of Nitroglycerine, Scopalamine, Clonidine, Estradiol

    For diagram refer KD Tripathi Text book

b)                 Conjuctival: into the conjuctiva for local effects eg: Sulfacetamide

c)                  Vaginal and Urethral: Pessaries are used for local actions

d)                 Inunction (Rubbing): rubbing onto the skin

 

Newer Drug Delivery Systems: To improve drug delivery and to prolong its duration of action, special drug delivery systems have recently been developed.

    These include: Ocuserts, Progestaserts, Transdermal Adhesive Patches, Prodrugs, Computerised Miniature Pumps, Use of Monoclonal Antibodies and Liposomes as drug carriers.

 

 

 

 

ADJUVANTS

ADJUVANTS

These are the substances which are other than the active

medicaments in the formulation which have no pharmacological action.

• Stabilizers
  

The stabilizers are the substances which ensure the final formulation.

e.g.:- Antioxidants

Preservatives

1. Antioxidants
   

   This prevents the oxidation reaction of a sensitive drug is called antioxidant.
   

Action

Reducing agent,

By breaking the oxygen chain reaction.

e.g.:-Ascorbic acid, sodium bisulfate, sodium metabisulfate, sodium thiosulfate.

Mechanism:-A free molecule is having three radicals which tend to bond or oxidize

 

 

reduction

In other mechanism the radical chain is inhibited by breaking

up the radical chain.

Properties:-

• It should be effective in low concentrations.
  
• It should not react with any other substance, compounds.
  
• It should not impact colour, odour, and taste, to the final formulation.
  
• lt should be effective in wide range of pH
  
• It should not be toxic & irritant to final formulation and
  

  skin.
  

  
   

  
   

  Examples:-
  

  Tocopheral
  

  It is soluble in water.
  

  It is obtained from vegetable oils.
  

  It is used in liquid paraffin.
  

  Gallic acid and Gallate
  

  It is soluble in water &Estoberic gallic acid.
  

  It is used for prevention of food, oils, perfume.
  

  Butylated hydroxy anised (BHA)
  

  2% BHA     For preservation and stabilization
  

  6% Propyl gallate    of food & cosmetics
  

  4% Citric acid
  

  70% Propylene glycol
  

 

Ascorbic acid:-

Preservation of fat & oils.

1. Preservatives
   

The substance which add to the preparation to prevent the bacterial growth.

1. Action
   

Bioavailability Studies

Definitions

Bioavailability [Shargel and Yu, 1985] indicates a measurement of the rate and extent (amount) of therapeutically active drug which reaches the general circulation.

Pharmaceutical Equivalent [Federal Register 1977] means drug products that contain identical amounts of the identical active drug ingredient, i.e., the salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and where applicable, content uniformity, disintegration times and/or dissolution rate.
Pharmaceutical Alternatives [Federal Register 1977] means drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
Therapeutic Equivalents Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.
Bioequivalent Drug Products [Federal Register 1977] means pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may be equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on chronic use, or are considered medically insignificant for the particular drug product studied == Therapeutic Equivalents.
Bioequivalence Requirement [Federal Register 1977] means a requirement imposed by the Food and Drug Administration for the in vitro and/or in vivo testing of specified drug products which must be satisfied as a condition of marketing.
Brand Name [Shargel and Yu, 1985] is the trade name of the drug.
Chemical Name [Shargel and Yu, 1985] is the name used by the organic chemist to indicate the chemical structure of the drug.
Drug Product [Federal Register 1977] means a finished dosage form, e.g., tablet, capsule, or solution, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients.
Generic Name [Shargel and Yu, 1985] is the established, non proprietary or common name of the active drug in a drug product.

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Past Bioavailability Problems

There are a number of examples of drugs products which have exhibited bioavailability problems in the past. These examples are all pre-1976 and as mentioned in the text were included in the earlier edition of the book with no further examples reported [Gibaldi, 1984]. This is an indication that more attention is now being given to formulation development during drug development. More recent example may be found by searching the FDA Enforcement Pages.

Figure 21.3.1 Plot of Cp versus Time

Chlorpropamide. With three products tested the peak plasma concentration after one brand was less than 1/2 the peak after the other two products (see Figure 21.3.1).
Digoxin. The text reports a number of bioavailability problems with digoxin. One example is particularly interesting. Doctors in Israel noticed 15 cases of digoxin toxicity between Oct/Dec 1975 with almost no reports for the same period the previous year. It was found that the local manufacturer had changed the formulation to improve dissolution without telling the physicians. Urinary data suggested a two-fold increase in availability of the new formulation.
Phenytoin. Again there are a number of examples in the text. One report described an incidence of phenytoin intoxication in Australia in 1968 and 1969. Apparently the tablet diluent was changed from calcium sulfate to lactose. Later studies showed that the bioavailability was higher from the dosage form containing lactose.
Other drugs with problems in the past include Acetazolamide, Aminosalicylate, Ampicillin, Aspirin, Ascorbic Acid, Chloramphenicol, Chlorothiazide, Diazepam, Furosemide, Iron, Levodopa, + 10.

Bioavailability - Bioequivalence Studies

Bioavailability studies are designed to determine either an absolute bioavailability (relative to an IV formulation) or relative bioavailability (with an alternate reference dosage form with good absorption characteristics). They can be used to compare different routes of administration, for example oral versus IV or IP versus IM.

Bioequivalence studies are designed to compare drug products. The objective is to determine if these products are bioequivalent. The dosage forms should be similar, especially the route of administration. For example, tablet versus tablet or maybe tablet versus capsule, given orally. These studies may be necessary before a generic product may be marketed. In general a relative bioavailability is determined which may be close to 100%.

Reasons for Bioequivalence Requirements

The FDA may decide to require bioavailability studies for a variety of reasons including:

• Results from clinical studies indicate that different drug products produce different therapeutics results.
• Results from bioavailability studies indicate that different products are not bioequivalent.
• Drug has a narrow therapeutic range.
• Low solubility and/or large dose.
• Absorption is considerably less than 100%

Bioavailability study characteristics

With recently introduced products properly conducted bioavailability studies will have been performed before the product is allowed to be marketed. However products which were approved some time ago may not have been tested as thoroughly. It is therefore helpful to be able to evaluate the testing which may have been undertaken. There are a number of situations where a pharmacist is required to evaluate bioavailability study testing. When selecting drug products for a prescription, product performance should be a most important criteria. Once it is established that two or more products are equivalent, then the choice of brand can be made on the basis of economic factors, cost etc.

The evaluation of a drug product bioavailability study involves the consideration of various factors.

Drug

The drug substance in each product must be the same. Bioavailability studies are conducted to compare two or more products containing the same chemical substance. We can't compare different chemical substances. The apparent volume of distribution and kel can be quite different for different drug substances, thus no interpretation of the results is possible. The first rule of bioavailability testing is that you compare the drug products with the same drug in each dosage from.

The only time that this rule is relaxed is in the case of pro-drug administration. A pro-drug is a compound which will form the drug of interest in the body. In this case it may be appropriate to compare the delivery of a dosage form containing the drug with another dosage form containing a pro-drug. This testing is generally conducted to evaluate the usefulness of the pro-drug, rather than a strict comparison of the drug products. Once the usefulness of the pro-drug is demonstrated comparisons between dosage forms all containing the pro-drug should be undertaken to evaluate the drug product performance.

Drug product

Figure 21.4.1 Plot of Cp versus Time after IV and IM Administration. NOTE: AUC are the same

Usually the comparison is made between two (or more) similar products, containing exactly the same chemical substance. However, different dosage forms can be compared (when they contain the same drug). For example we could compare an IM dosage form with an IV one.
By calculating the AUC values we can determine the absolute bioavailability of the IM dosage form. In this case it appears to be close to 100%. The rate of absorption for the IM dose can be determined also, but of course no comparison is possible.

Figure 21.4.2 Plot of Cp versus Time for A and B with B having Slower Absorption

Alternately we could compare brand A tablet with brand B tablet or capsule.
By comparing the AUC values and ka values we can make comparisons concerning both the extent and rate of absorption. In this case A appears to be faster than B but the extent of absorption doesn't appear to be all that different.

Subjects

A number of factor are of concern; health, age, weight, enzyme status, number. Studies with humans must be carefully evaluated and approved by an Institutional Review Board (IRB). There must be an optimal risk/benefit ratio and given that in most bioavailability studies (with healthy volunteers) there is little direct benefit to the individual any risks should be minimal. All subjects must give informed consent, that includes a requirement that they be provided with clear descriptions of their risks and benefit to participation.

Health

Usually a study is designed so that each subject takes each product in turn. Thus the effect of the individual subject can be eliminated or reduced. Such a study design is called a cross- over design. Even though each subject will act as their own control it is usually best to have subjects of similar kinetic characteristic so that major variations are not introduced. Thus healthy volunteers are often preferred by drug product evaluation studies. Informed consent should be obtained from each volunteer and some biochemical and medical examination will be used to confirm their medical state. For some drugs there may be special disease states which may cause the exclusion of some volunteers. For example, in one study we looked at propranolol products, and otherwise healthy volunteers with a past history of asthma were excluded from this study.

Age

As you will see later, age can have a significant effect on drug pharmacokinetics. Elderly patients and young children can have quite different kinetics compared with young adults. In the interest of a better matched group, subjects between the ages of 18 to 35 years are preferred. Kinetic changes usually aren't important until age greater than 60.

Weight

The apparent volume of distribution is usually proportional to weight in subjects of normal weight for height. However, in overweight (or underweight) subjects the V in L/kg maybe somewhat different. Again to better match the subjects, normal weights are preferred.

Enzyme status

Smokers or subjects taking certain other drugs may have altered kinetics for the drug of interest. This can be caused by alteration of enzyme activity or by drug-drug interactions. These effects add complications to a study and an attempt is usually made to minimize these factors.

Number

The number of subjects included in the study should be sufficient to see any real (maybe 20% variation) differences in bioavailability. Usually 10 - 20 subjects are used in these studies. In clinical studies where the end-point is some clinical response, much larger numbers are required because of the greater variability in clinical response.

Assay

The same assay method should be used for all phases of the study. It is not much use using one assay for product A samples and another assay for product B samples. This wouldn't be done in a single study, however, if you were trying to compare the results from one study with those from another, different assay methods may have been used. One assay method may pick up an interference which is not indicative of the drug concentration or the bioavailability. Also the assay method should be sensitive and specific.

Design

Usually a complete cross-over design is used. With this design each subject receives all products with a wash-out period between each dose administration.

Figure 21.4.3 Figure Showing Concentrations After Two Separate Drug Administrations

Table 21.4.1 Two Product Example

	Week 1	Week 2
Group 1	A	B
Group 2	B	A	for two products

Table 21.4.2 Three Product Example

	Week 1	Week 2	Week 3
Group 1	A	B	C
Group 2	B	C	A
Group 3	C	A	B
Group 4	A	C	B
Group 5	C	B	A
Group 6	B	A	C	for three products

When more than 3 or 4 products are involved it has been suggested that a different design is used whereby each subject will get maybe 3 or 4 products of a possible 8 to 12. This type of design, possibly an incomplete block design, usually requires more subjects to get the same information, but it does mean that each subject is not required to take as many doses. It is harder to recruit subjects for longer studies.

Data analysis

Statistics

The rate of absorption can be characterized by the ka value and also the time of peak concentration. The extent of drug absorption is characterized by the F value or the peak concentration or total AUC values. Any differences in the average values of these parameters can then be analyzed statistically to determine the significance of the differences. The 5 % confidence levels is usually used as the criteria of acceptance. The analysis of variance is a technique for separating the effect of product, subject, and sequence. The significance of each of these factors can be tested.

Table 21.4.3 Analysis of Variance Table for Three-Way Cross-Over Study

Source of Variation	d.f.	SS	MS	F	Significance Level
Total	35	44.6	-	-	-
Subject	11	28.3	2.58	10.1	p < 0.001
Week	2	0.14	0.068	0.27	n.s.
Treatment	2	11.0	5.55	21.8	P < 0.001
Residual	20	5.09	0.255	-	-

In this example two effects are significant. There appears to be a significant effect due to treatment and subject. This would indicate that the subjects are significantly different from each other and that the treatments are significantly different in terms of the parameter measured. It is quite common that Cp or AUC values are significantly different for different subjects, because of their different weights or size. The different treatments would appear to be bio-inequivalent.
By these studies the relative bioavailability of two or more products can be determined. Hopefully with proper testing we can ensure that drug products labeled to contain equivalent chemical amounts will be bioequivalent as well.

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Generate typical data from a simulated bioavailability study and analyse the data using an Analysis of Variance (ANOVA).