Drug Incompatibility

Drug Incompatibility Pharmaceutical incompatibility of a drug refers to interactions between two or more substances which lead to changes in chemical, physical and therapeutic properties of the drug or its dosage form.
Incompatibility occurs as a result of mixing of two or more “Antagonistic Substances” & an undesirable product is formed which may affect the safety, efficacy & appearance of the pharmaceutical preparation.

Incompatibilities are usually unintentional.

It may occur in vitro between drugs & other components during preparation, storage or administration.

Types of Drug Incompatibility

There are three types of drug incompatibilities-

1. Therapeutic incompatibility

2. Physical incompatibility

3. Chemical incompatibility

Therapeutic Incompatibility

It is the modification of the therapeutic effect of one drug due to the prior concomitant administration of another, or it may occur due to overdose or wrong dose of the drug being prescribed. Basically the interaction can alter the pharmacokinetic or pharmacodynamic property of the drug.

Pharmacokinetics interactions involve alteration of absorption, distribution, metabolism and excretion of the drug 

Pharmacodynamics interactions involve modulation of pharmacological response resulting in synergistic, antagonistic, potentiation or additive response. This can also lead to altered cellular drug transport.

Examples:

1. Tetracycline interacts with milk forming unabsorbed complex (altered absorption).

2. Antibiotics kill large number of normal flora of intestine, thus drugs like digoxin when given with antibiotics, toxicity appears due to altered metabolism of digoxin.

3. Sulphonamide displaces warfarin thus leading to bleeding (altered distribution).

4. Penicillin and tetracycline are weak acid and are unionized in acidic pH thus are reabsorbed in the body (altered excretion)

5. Caffeine oral increases and chloral hydrate oral decreases sedation and drowsiness, thus two should not be prescribed together.

Physical Incompatibility

Physical incompatibility is the result of interaction between two or more substances which lead to change in color, odor, taste, viscosity and morphology. It can occur due to insolubility of prescribed agent in vehicle, immiscibility of two or more liquids or liquification of solids mixed in a dry state (called eutexia). The solubility of the drug can be altered due to change in pH, milling, use of surfactant, chemical reaction, complex formation and co-solvent used.

Examples:

1. Benzalkonium chloride and sodium lauryl sulfate when are mixed, a precipitate is formed because benzalkonium chloride is positive charged while sodium lauryl sulfate has negative charge.

2. A prescription containing Ephedrine sulfate, menthol and liquid paraffin is incompatible due to ephedrine sulphate , a salt soluble in water not in organic solvents, oil and paraffin.

Immiscibility appears in emulsion, creams, lotions and ointments In can happen due to incomplete mixing, addition of surfactants, presence of microorganism or change in temperature. Liquefaction, a physical incompatibility occurs when two solid substances are mixed together, conversion to a liquid state takes place.

The reasons for liquefaction are

(i) When the solid substance is soluble in another solid substance, decrease of its melting point and conversion to a liquid take place.

(ii) By mixing hydrated crystals and dry crystals, crystalline water diffuses to dry crystals leading to formation of liquid.

Chemical Incompatibility

Chemical incompatibility is a reaction between two or more substances which lead to change in chemical properties of drug or its pharmaceutical dosage form. It can occur due to oxidation, hydrolysis, polymerization, isomerization, decarboxylation, absorption of CO2, combination or formation of insoluble complexes.

Chemical incompatibility is of two types:

Tolerated Chemical Incompatbility: 

The incompatability is minimized by changing the order of mixing not the components.

Adjusted Chemical Incompatability:

Here addition or substitution of interacting component is done without affecting the efficacy. In sodium salicylate mixture, syrup of lemon is used as flavorant, it reacts with sodium salicylate, forming an insoluble salicylic acid, thus instead of syrup of lemon, tincture of lemon can be used.

Some other examples of such type of incompatibility include:

Examples:

1. Phenylephrine shows change in color due to oxidation.

2. Penicillin G sodium is affected by acidic condition created syrup of cherry and thus an indiffusible penicillinoic acid is formed which is an inactive product.

3. Potassium chlorate-tannic acid formulation is explosive, therefore minimal rubbing is required 4. Sodium bicarbonate-borax-glycerin preparation leads to evolution of carbon dioxide, therefore formulation must be dispensed once the gas is ceased down.

Intentional Incompatibilities

Intentional incompatibilities are observed in some prescriptions, which are done to modify the activity of one in presence of other.

Examples:

1. Atropine and morphine prescribed together, the former should antagonize the depressant effect of morphine to the respiratory tract.

2. A mild laxative antacid such as Mg(OH)2 may be used to overcome the constipating effect of an astringent antacid such as AL(OH)3.

3. Tincture myrh is diluted with water to give a precipitate which is used as a gargle in the treatment of tonsillitis.

      Related reading :- Drug Incompatibility (Click here to download pdf)

Dissolution Apparatus

• Dissolution is the physicochemical process by which a solid substance enters the solvent phase to yield a solution. Dissolution (release of the drug from the dosage form) is a key pre-requisite for any orally administered drug to be systemically effective. 
• It is a dynamic process.
• Dissolution is defined as the process by which a known amount of drug substance goes in to solution per unit time under standaridized condition. 

Important dissolution factors can be identified by Noyes Whitney equation:

  dC  ‗ D.A Ko/w (Cs-Cb)

   dt      v h

Where dC/dt is a rate of drug dissolution at time‘t’
A = surface area of the particle, h=thickness of the stagnant film layer
Cs - Cb=concentration of gradient of diffusion of drug.
K=water/oil partition coefficient.
D=1/N X (VA); D=diffusion coefficient of compound in the medium
Where N= solvent viscosity

 VA = Solute molecular volume

Intrinsic dissolution rate

• Intrinsic dissolution rate (IDR) of a pure substance is the rate at which it dissolves from a constant surface area whilst the temperature , agitation , pH and ionic strength of the dissolution medium are kept constant. 
• Dissolution rate refers to the rate at which the solid dissolves in a solvent. 
• IDR≥ 1.0mg/min/sq.cm suggests drug dissolution will not be the rate limitting step . 
• IDR ≤0.1mg/min/sq.cm suggests drug dissolution will be the rate limitting step .

 
Apparatus to measure IDR

1. Wood apparatus : rotating disk 
2. Stationary disk apparatus

Need of Dissolution testing devices

• Solid drugs absorbed only from the solution . 
• In vitro test – estimate amount of drug released per unit time. 
• In vitro disintegration test not sufficient . 
• In vitro dissolution test most reliable predictors of in vivo performance. 
• Dissolution - rate limiting factor. 

Common conditions

• Simulated gastric and intestinal fluids – 37 deg Celsius 
• Fixed speed agitator 
• Screen for separation of disintegrated particles from the bulk 

USP Apparatus

Classification of dissolution apparatus in different pharmacopeias:

Diffusion

Diffusion the movement of particles in a solid from an area of high concentration to an area of low concentration, resulting in the uniform  distribution of the substance 

Diffusion refers to the process by which molecules intermingle as a result of their kinetic energy of random motion. Consider two containers of gas A and B separated by a partition. The molecules of both gases are in constant motion and make numerous collisions with the partition.

Diffusion is process which is NOT due to the action of a force, but a result of 

the random movements of atoms (statistical problem)

Osmosis

Osmosis is the spontaneous net movement of solvent molecules through a semipermeable membrane into a region of higher solute concentration, in the direction that tends to equalize the solute concentrations on the two sides. It may also be used to describe a physical process in which any solvent moves across a semipermeable membrane (permeable to the solvent, but not the solute) separating two solutions of different concentrations. 

           

Tonicity

 Tonicity is a measure of the effective osmotic pressure gradient (as defined by the water potential of the two solutions) of two solutions separated by a semipermeable membrane. In other words, tonicity is the relative concentration of solutions that determine the direction and extent of diffusion.

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Steady state diffusion

 Fick’s first law of diffusion

For steady-state diffusion condition (no change in the system with time), the net flow of atoms is equal to the diffusivity Dtimes the diffusion gradient dC/dx

Non-Steady-State Diffusion

In practice the concentrationof solute atoms at any point in the material changes with time–non-steady-state diffusion

For non-steady-state condition, diffusion coefficient, D- NOT dependent on time

PROCEDURES AND APPARATUS

A number of experimental methods and diffusion cells have been reported in the literature. Examples of those used mainly in pharmaceutical and biologic transport studies are introduced here.

Cells of simple construction, such asthe one reported by Karth et al. are probably best for diffusion work.

 They are made of glass or clear plastic, are easy to assemble and clean, and allow visibility of the liquids and rotating stirrer.

They may be thermostated and lend themselves to automatic sample collection and assay. The donor chamber is filled with drug solution. 

Samples are collected from  the  receptor compartment in an automatic fraction collector and subsequently assayed spectrophotometrically.

Experiments may be run for hours under these controlled conditions.

Biber and Rhodes constructed a Plexiglas three­compartment diffusion cellfor use with either synthetic or isolated biologic membranes.

The drug was, allowed to diffuse from the two outer donor compartments in a central receptor chamber.

Results were reproducible and compared favorably with those from other workers.

The three-compartment design created greater membrane surface exposure and improved analytic sensitivity.

The permeation through plastic film of water vapor and of aromatic organic compounds from aqueous solution may,be investigated in two-chamber glass cells similar in design to  those  used for  studying drug solutions in  general.

Nasim et al. reported on the permeation, of aromatic compounds from aqueous. solution through polyethylene films.

Higuchi and Aguiar studied the permeability of water vapor through enteric coating materials using a glass diffusion celland a McLeod gauge to measure changesin pressure across the film.

Simple diffusion cell.

 (After M. G. Karth, W. I. Higuchi and J. L. Fox, J.  Phann. Sci. 74, 612, 1985, reproduced with permission of the copyright owner.)

Diffusion cell for permeationthrough stripped skin layers.

The penneant may be in the form of a gas, liquid, or gel. Key:A, glass stopper; B, glass chamber; C, aluminum collar; D, membrane and sample holder. (From D. E. Wurster, J. A. Ostrenga and L. E. Matheson, Jr., J. Pharm. Sci. 68, 1406, 1410, 1979, reproduced with permission of the copyright owner.

The sorption of gases and vapors may be determined by use of a microbalance enclosed in a temperature controlled and  evacuated vessel that is capable of weighing within a sensitivity of ±2 x 10-6 g. The gas or vapor is introduced at controlled pressures into  the glass chamber containing the polymer or biologic film of known dimensions,  suspended on one arm of the balance. The mass of diffusant sorbed at various pressures by the film is recorded directly.

The rate of approach to equilibrium sorption permits easy calculation of the diffusion coefficients for gases and vapors. In studying percutaneous absorption, animal or human skin, ordinarily obtained by autopsy, is employed.

Scheuplein" described a cell for skin  penetration experiments made of Pyrex and  consisting of two halves, adonor and a receptor chamber, separated by a sample of skin supported on a perforated plate and securely clamped in place.

The liquid in the receptor was stirred by a Teflon-coated bar magnet.

The apparatus was submerged in a constant-temperature bath, and samples were removed periodically and assayed by appropriate means.

 For compounds such as steroids, penetration was slow, and radioactive methods were found necessary to determine the low concentrations. Wurster et al. developed a permeability cell to  study the diffusion through stratum corneum (stripped from the human forearm) of various permeants, including gases, liquids, and gels.

The  permeability cell .

During diffusion experiments it was kept at constant temperature and gently shaken in the plane of the membrane.

Samples. were withdrawn from  the  receptor chamber at definite  times  and analyzed for the permeant. The kinetics and  equilibria of liquid and solute absorption 'into  plastics, skin, and chemical and other biologicmaterials may be determined simply by placing sections of the film in a constant-temperature bath of the pure liquid or solution. The sections are retrieved at various times, excess liquid is removed with absorbant tissue, and the film samples are accurately weighed in tared weighing bottles. A radioactive-counting technique also may be used with this method to analyze for drug remaining in  solution and, by difference, the amount sorbed into the film.  . Partition coefficients are determined simply by equilibrating the drug between two immiscible solventsin a suitable vessel at a constant temperature and removing samples from both phases, if possible, for analysis.

Addicks et al described a new flow-through cell, Grass and Sweetana" proposed a diffusion cell for the study of gastrointestinal permeation, and Addicks et al designed a cell that yields results more comparable to  the  diffusion of drugs under clinical conditions. Equilibrium solubilities of drug solutes are also' required in diffusion studies.