Influence of particle size

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INFLUENCE OF PARTICLE SIZE ON PERFORMANCE OF A DRUG DELIVERY SYSTEM

Particle size of the active pharmaceutical ingredient (API) and inert excipients are to be considered in pre-formulation, design of drug delivery system as it is influencing the proceessability, stability, bioavailability and efficacy of drug delivery system. This article is aimed to highlight the significance of particle size on efficacy/ performance of various dosage forms.

1. Solid dosage forms:

Conventional solid dosage forms such as tablets are administered orally for local and systemic action. The local activity (acid neutralizing capacity) attributed by antacid formulations is proportional to the particle size of the ingredient 1.
Particle size is having a pronounced effect on the absorption of drugs with low aqueous solubility. This was demonstrated with tablets, capsules, suspensions and suppository dosage forms and reported for griseofulvin, chloramphenicol etc. The formulations containing chloramphenicol having particle size of 50-200u showed higher absorption compared to the chloramphenicol formulations having particle size of 400-800u 2.

Particle size of excipients:

The particle size of disintegrants like starch influences the disintegration time of the tablets. Starch grains with large particle size are more efficient disintegrants 3.The efficacy of lubricant is also influenced by the particle size and lubricants having a particle size of 60-100 mesh are used most often 4. The dissolution rate of an insoluble drug is influenced by the particle size of the filler and it's affect on solubility of the drug5.
E.g.: The particle size of lactose employed can affect the release rate of drug. The T50% was decreased by a factor of 8 when micronized lactose was used rather than non-micronized lactose.
Particle size of pellets employed for sustained release:
Larger size pellets are more preferable for sustained/extended release. We observed that the pellets having a size of 10/16 offered relatively low release of diclofenac compared to 22/44 size 6.

2. Particle size in parenterals:

Syringeability and injectability properties of a parenteral suspension are closely related to the particle characteristics of the parenteral suspension. The rate of reconstitution from a drug powder to form aqueous solution/suspension is influenced by the particle size. To minimize pain and tissue irritation, the particle size of the dispersed phase should be below 10um 7.
The rate of release of drug present in oily phase of an emulsion is described by the following equation 8.
Rate of release of drug
Where, a0 is the initial radius of the droplet.
The rate of disappearance of a drug from the aqueous phase of the emulsion is influenced by the parameters furnished in the following equation9.

Where, A is surface area of the droplet.
Influence of particle size of dispersed phase on duration of action is summarized in the following table 10, 11:
Table.1: Effect of particle size on duration of action of Insulin
Type of Insulin suspension Particle size (um) Duration of action (hrs)
Neutral Protamine Hagedron insulin(NPH) 30 24-28
Prompt insulin zinc suspension (Semi lente) 2 10-16
Lente Insulin 10-40 12-18
Ultra Lente Insulin (Extended insulin zinc suspension) 10-40 18-36

3. Particle size in ophthalmic formulations:

The residence time and duration of action, discomfort & irritating potential, rate of release and absorption from eye suspensions and eye ointments depends up on the particle size of the dispersed drug. The efficacy of novel occular drug delivery systems such as neosomes, discomes, pharmacosomes, and nanoparticles also depends up on the particle size of such carriers.

4. Particle size in aerosols:

Micronized drug is one of the essential requirements for dry powder inhalers. The ratio of fine and coarse lactose influences the performance of drug powder inhalers. From our studies on aerosols, it was concluded that 10% of fine lactose and 90% coarse lactose blend is suitable as carrier for development of dry powder inhaler12.

5. Particle size in semisolid dosage forms:

Particle size of the pharmaceutical semi-solid dosage forms influences the efficacy, safety and performance of the dosage form. It affects skin penetration and can also influence the flux rate of the active ingredient. In addition, particle size is a key factor in determining processability, spreadability and the rheological behavior of a formulation. The spreadability decreases with decreasing particle size due to the presence of high particle-particle interactions 13-15. Influence of particle size of semi-solid dosage form on absorption is summarized in the following table:
Table.2: Effect of particle size of semi-solid dosage form on penetrability of dosage form.
Particle size Region of absorption
3-10um follicular ducts
>10um remains on the skin

6. Particle size in targeted drug delivery:

The targeting potential of particulate drug delivery is influenced by the particle size of the liposomes, niosomes, and such other colloidal particles16- 17 and the relationship is showed in the following table.

Table.3: Influence of particle size on targetability.
Particle size Targeted organ
Liposomes
1-8um Liver and spleen
7-13 um Lung
>13 um First vasculature
Niosomes
100nm Topical
Discomes
16 um Ocular

7. Particle size in biological stability:

Particle size may also play an important role in stability of drug in biological environment. Penicillin G and Erythromycin are unstable in gastric fluids. Reduction in particle size and improvement of dissolution rate are result in extensive degradation of the drugs and low bioavailability18.

8.Particle size in safety:

Reduction in particle size of drug results in improvement of the rate& extent of oral absorption but such improvement in bioavailability can result in an increased incidence of side effects19.
Examples for such drugs: Digoxin, Nitrofurantoin, Medroxy progesterone, Danazol, Tolbutamide, Aspirin, Naproxen, Ibuprofen, Phenacetin.
Gastrointestinal micro bleeding of aspirin decreases as the particle size of the formulation declines 20.

References:

1.Satyanarayana V, Srikavitha K, Chowdary Y.A, Murthy T.E.G.K, The antiseptic,103(2),73-75,2006.
2. Finholt P.In: Leeson LJ, Cartensen TJ,eds.Dissolution technology,Washington DC:APHA,1974,108.
3. A.J.Smallon brock, G.K.Bolhuis and C.F.Lerk, Prarm.week bl., Sci, Ed., 3, 172, 1981.
4. Edward M Rudnic,Joseph B Schwarts In: Remington The Science and practice of pharmacy ,21st edition,vol 1,2005,892.
5. Herbert A. Lieberman, Leon Lachman, Joseph B. Schwartz, PHARMACEUTICAL DOSAGE FORMS Tablets, 2nd Edition, REVISED AND EXPANDED, Volume 1, Published by Informa Healthcare, Page. No: 97-98
6. T.E.G.K.Murthy and KPR Chowdary, Formulation and evaluation of ethyl cellulose coated diclofenac sodium microcapsules: Influence of solvents,Indian J.Pharm.Sci.,2005,67(2):216-219.
7. R.E.Collard, Formulation and manufacture of corticosteroid preparations, Pharm.J, 186, 133 (1961).
8. W.I. Higuchi, Rate of solute transport out of emulsion droplets in micron size range, J.Pharm.Sci, 53, 405, 1964.
9. J.L.Windheuser, M.L.Best and J.H. Perrin, Evaluation of sustained acting parenterals, parent, Drug Assoc. Bull.,24,286 (1970).
10. http://www.auburn.edu/~deruija/insulin_preparations.pdf; accessed on 09/02/2011.
11. Edward M Rudnic,Joseph B Schwarts In: Remington The Science and practice of pharmacy ,21st edition,vol 2,2007,1450-1452.
12. T.E.G.K.Murthy, M. Bala Vishnu Priya and V. Satyanarayana Formulation and evaluation of dry powder inhaler for tritropium Bromide, International Journal of innovative Pharmaceutical research, 2010, 1(1), 14-22.
13. http://www.malvern.com/semi_solids_sizing; accessed on 11/02/2011.
14. Piyush Gupta and Sanjay Garg, Recent Advances in Semisolid Dosage Forms for
Dermatological Application, Pharmaceutical Technology, March, 2002, 144-162.
15. Soheila Honary, M Chaigani, A Majidian, The effect of particle properties on the semisolid spreadability of pharmaceutical pastes, Indian journal of pharmaceutical sciences, 69 (3), 2007, 423-426.
16. Vladimir P. Torchilin, NANOPARTICULATES AS DRUG CARRIERS, Imperial College Press, London, 2006, 113-117.
17. S.P. Vyas and R.K. Khar, Targeted and controlled drug delivery novel carrier systems, 578.
18. Michael E. Aulton, Pharmaceutics: The design and manufacture of medicines, 3rd edition, 2007,288.
19. Milo Gibaldi, Biopharmaceutics and clinical pharmacokinetics, 4th edition, 2006, 51
20. J.R. Leonards and G.levy, Biopharmaceutical aspects of aspirin-induced blood loss in man, J.pharm.Sci, 58, 1277, (1969).

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Siva Mavuduru's picture

Really excellent blog sir you presentation made me understand properly sir,equations for the drug release and drug disappearance are missing in "particle size in parenterals" concept.

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