Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
INTRODUCTION
INCOMPATIBILITY -Definition -3 Types OBJECTIVE OF THE STUDY -Why to screen excipients? 1.need to minimize no of model formulations 2.provide rational basis for selecting excipients 3.Formulation stability studies are time consuming. -Goal of the study( Identify the excipients that) 1.are compatible with API 2.do not have impact on the stability of API -Importance 1.Stabity of formulation can be maximised. 2.Helps to avoid surprise problems. 3.Essential for IND submission. 4.Bridges drug discovery and drug development
COMPATIBILITY TESTS
2 Aspects of compatibility tests are: 1. Identification of compatible excipients for a formulation. 2. Identification of stable storage conditions 2 Types:
- much slower and difficult to interpret. - easier to detect - Acc. to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions 1. Acidic or alkaline pH. 2. Presence of added substances 3. High oxygen and nitrogen atmospheres. 4. Effect of stress testing conditions.
SAMPLE PREPARATION
FOR SOLID STATE REACTIONS: SampleA: -mixture of drug and excipient SampleB: -SampleA+ 5% moisture SampleC: -Drug itself without excipients
o o o o o o
All the samples of drug-excipient blends are kept for 1-3 weeks at specified storage conditions. Then sample is physically observed . It is then assayed by TLC or HPLC or DSC. Whenever feasible, the degradation product are identified by MASS SPECTROSCOPY, NMR or other relevant analytical techniques. To determine Solid state stability profile of a new compound. To test the Surface Oxidation..
SAMPLE PREPARATION
FOR LIQUID STATE REACTIONS: o Place the drug in the solution of additives. o Both flint and amber vials are used. o This will provide information about
o In case of oral liquids, compatibility with ethanol, glycerin ,sucrose, preservatives and buffers are usually carried out.
STORAGE CONDITION
The storage conditions used to examine compatibility can very widely in term of temp. & humidity, but a temp. of 50c for storage of compatibility sample is considered appropriate. Some compounds may require high temp. to make reaction proceed at a rate that can be measured over a convenient time period.
Accelerated Stability Study FT-IR Spectroscopy DRS-Diffuse Reflectance Spectroscopy Chromatography SIC-Self Interactive Chromatography TLC-Thin Layer Chromatography HPLC-High Pressure Liquid Chromatography Radiolabelled Techniques Vapour Pressure Osmometry Flourescence Spectroscopy
11. Miscellaneous
Trace 1 of figure 1-4 shows peak at 278.330C. (melting endothermic peak of Ofloxacin). Trace 3 (Physical mixture of Ofloxacin & Lactose) shows absence of peak at 278.330C and slight pre shift in Lactose peaks. DSC RESULT-- INCOMPATIBLE
Trace 5 (Physical mixture of Ofloxacin & Starch) shows an early onset at 268.370C. But no other changes in thermogram. DSC RESULT-- COMPATIBLE
Trace 7 (Physical mixture of Ofloxacin & PVP) shows no change in position of endothermic peak for PVP but there is increase in peak area and size & shape of peak for Ofloxacin is also decreased. DSC RESULT-- INCOMPATIBLE
Trace 9 (Physical mixture of Ofloxacin & Talc) shows combine features of each component but there are evident changes in onset. DSC RESULT-- COMPATIBLE
LIMITATIONS OF DSC
o If thermal changes are very small, DSC cant be used. o DSC can not detect the incompatibilities which occur after long term storage. Eg. MCC / ASPIRIN o Not applicable if test material exhibits properties that make data interpretation difficult. o ADVANTAGES: -Fast -Reliable and very less sample required.
(Ref:I.J.P.E.,Jan:2000,153)
PRINCIPLE:For different mobile phases (i.e. different excipients) the injected drug have different interactions (may be repulsive or attractive) with the SP of drug leads to shift in retention time ( Rt)
FIGURE-1
FIGURE-2
FIGURE-3
When attractive interactions,it will have longer retention time& wider peak
INCOMPATIBLE IMPURITIES
o Chemical impurity profiles -Very important in influencing the long term chemical stability. Eg:(1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical excipients. POVIDONE PEG 400 HPC POLYSORBATE 80 Contains substantial conc. of HPOs with significant batch to batch or mfger to mfger variations.
o While MCC, Lactose, High M.wt PEG, Polyxamer contains less amt. of HPOs. o 5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high HPO content.
(Ref: J.Ph.Sci,vol:97,Jan:2007,106)
(2) DCP Sometimes, IRON may be present in DCP as impurities. It is incompatible with MECLIZINE HCl . (Fe NMT 0.04%) (3)Gelatin is also containing IRON as impurities, Dark spots may occur in the shell due to the migration of water soluble iron sensitive ingredients from fill material into the shell.
Known Incompatibilities
Functional group Primary amine Ester, Lactone Aldehyde Carboxyl Alcohol Sulfhydryl Phenol Gelatin- Capsule Shell Incompatibility Mono & Di-saccharides Basic component Amine, Carbohydrate Base Oxygen Oxygen Metal Cationic Surfactant Type of reaction Amine-Aldehyde & Amine-Acetal Ester base hydrolysis, opening, Ring
Aldehyde-Amine, Schiff base Or Glycosylamine formation Salt formation Oxidation to Aldehyde & Ketones Dimerization Complexation Denaturation
Excipient
Parabens
Incompatibility
Non ionic surfactants (Polysorbate 80) Plastic Containers
Type of reaction
Micellization (Reduced antimicrobial activity) Absorption of Parabens Anti-microbial activity Reduced Incompatible (forms less soluble halogen compds) Anti-bacterial activity reduced Softening & Liquifaction Discoloration Migration of PEG from tablet film coating, leading to interaction with core component
Phenylmercuric Nitrate
PEG
Penicillin & Bacitracin Phenol, Tannic acid & Salicylic acid Sulphonamide & Dithranol Film coating
o Millard reaction:- is a non-enzymatic bimolecular browning reaction between reducing sugar and an amine.(Anhydrous lactose: no Millard reaction) o Mechanism:-
Example2:-
o Anhydrous ethanol is corrisive to Al containers. -Hydrogen produced in the reaction increases the pressure of the container.So drugs containing polar solvents tend to be corrosive to bare Al. o For containers which contain 2%Tin and 98% Lead -Lead reacts with the fatty acids(for product cont.soaps) to form Lead salts which cause valve clogging.
Ascorbic acid: Incompatible with acid- unstable drugs Na bisulfite:+ Epinephrine Sulphonic acid dvt. -Incompatible in Opthalmic solution containing Phenyl mercuric acetate Edetate salts: Incompatible with Zn Insulin, Thiomerosal, Amphotericin & Hydralazine
Preservatives
Phenolic Preservatives -Lente- Insulin + Phenolic preservative Insulin structure. -Protamine- Insulin + Phenolic preservative responsible for prolong action of insulin. Break-down of Bi-sulphide Linkage in
One must concern about the residual peroxide present in Polysorbate. PS 80 PS 20 Polyoxyethylene sorbitan ester of Polyoxyethylene sorbitan ester of Oleic acid ( Unsatd.F.A) lauric acid ( Satd.F.A)
Cosolvants
Sorbitol Increase the degradation rate of Penicillin in Neutral and Aqueous solutions. Glycerol Increase the mobility of freeze-dried formulation leading to peptide deamidation.
COSOLVENTS
Sr . N o. DRUG EXCIPIENT Propylene-glycol Cremophor EL (polyoxyl 35 castor oil) INTERACTION OBSERVED Hemolysis (in vivo effect) Precipitation of Cremophor EL
Sr. No. 1.
2.
Protein formulations
Meta-cresol
Benzyl alcohol Benzyl alcohol caused the aggregation of the protein Sodium metabisulfite Sodium metabisulfite inactivates cisplatin
REFERENCES
Pharmaceutical Dosage forms By Leon Lachman & Liberman Hand book of Pharmaceutical Excipients Remingtons Pharmaceutical Science,21st edition,2005. Modern Pharmaceutics by Banker & Rhodes,4th edition,2002. Theory and Practice of Industrial Pharmacy by Lachman & Lieberman. Int. J. Ph.Exci., Vol-1, Jan-2000, 153. Int. J. Ph.Exci., Nov-2002, 2283 Int. J. Ph.Exci.,jan-march,2003 J. Ph. Sci..,Vol-97, Jan-2007,106 J. Ph. Sci., Vol-95, May-2006, 976. J. Ph. Sci., Vol-95, May-2006, 1060. J. Ph. Sci., Vol-95, June-2006, 1342. J. Ph. Sci., Vol-93, Jan-2004,132 J. Ph. Sci., Vol-93, Nov-2004, 2755. J. Ph. Sci., Vol-92, May-2003, 516. JPS 2002, Vol. 91, No. 9-12, page 2283-2296 C.A. vol:146, No:25,June 18 :2007,507180t C.A. vol:147, No:4, July 23 :2007,79121 CA,Vol:151,No:6, August10,2009 ,131557w