7. Drug-Excipient compatibility Study ma

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Importance of Drug Excipient Compatibility Study:- : 

Stability of the dosage form can be maximized. It helps to avoid the surprise problems. It bridges the Drug discovery and Drug development. DECS data is essential for IND (investigational new drug ) submission. 2 Importance of Drug Excipient Compatibility Study:-

Incompatibility- general aspects : 

Incompatibility- general aspects DEFINITION:- 3

Compatibility tests : 

# Aspects of above tests are- Identification of compatible excipients for a formulation Identification of stable storage conditions for drug in solid or liquid state. 4 Compatibility tests

A.Solid state reactions : 

5 A.Solid state reactions Solid state reactions are much slower and more difficult to interpret than solution state reactions.

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6 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 Weighed sample are placed in open screw cap vials and exposed directly to a variety of temp,, humidity & light intensities. To test the Surface Oxidation, Samples are stored in large (25 ml) vials for injection capped with a Teflon lined rubber stopper & headspace filled with dry oxygen.

Why drug itself is taken as one of the sample for Drug- excipient compatibility studies? : 

Organic synthesis of compound may lack the refinement and it is common that there will be several weak spots (of impurities) on a TLC chromatogram of a compound. Drug stability profile (effect of humidity, temp., pH, oxygen) helps in proper selection of excipients. It is now required by FDA for IND submission. 7 Why drug itself is taken as one of the sample for Drug- excipient compatibility studies?

Liquid state reactions : 

The program set up is same as solid dosage forms. Now according to “Stability guidelines” by FDA following conditions be evaluated in studies on solutions or suspensions of bulk drug substances. Acidic or alkaline pH. Presence of added substances- chelating agents, stabilizers etc. High Oxygen and Nitrogen atmospheres. Effect of stress testing conditions…… 8 Liquid state reactions


9 METHODOLOGY Place the drug in the solution of additives. Both flint and amber vials are used. This will provide information about Susceptibility to oxidation. Susceptibility to light exposure. Susceptibility to heavy metals. In case of oral liquids, compatibility with ethanol, glycerine sucrose, preservatives and buffers are usually carried out.

Analytical techniques used to detect Drug-Excipient Compatibility : 

Thermal methods of analysis DSC- Differential Scanning Calorimetry DTA- Differential Thermal Analysis Accelerated Stability Study FT-IR Spectroscopy DRS-Diffuse Reflectance Spectroscopy Chromatography SIC-Self Interactive Chromatography TLC-Thin Layer Chromatography HPLC-High Pressure Liquid Chromatography Miscellaneous Radiolabelled Techniques Vapour Pressure Osmometry Flourescence Spectroscopy 10 Analytical techniques used to detect Drug-Excipient Compatibility

DSC:Differential Scanning Calorimetry : 

DSC is widely used to investigate and predict any physico-chemical interaction between drug and excipients involving thermal changes.. METHOD The preformulation screening of drug-excipient interaction requires (1 : 1)Drug:excipient ratio, to maximize the likehood of observing an interaction. Mixture should be examined under N2 to eliminate oxidative and pyrrolytic effects at heating rate ( 2, 5 or 100 c / min) on DSC apparatus. 11 DSC:Differential Scanning Calorimetry

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Example : DSC in Ofloxacin tablets : 

Example : DSC in Ofloxacin tablets 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 (Ref: I.J.P.E. Oct-Dec:2002,97) 13

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Trace 5 (Physical mixture of Ofloxacin & Starch) shows an early onset at 268.370C. But no other changes in thermogram. DSC RESULT-- COMPATIBLE 14

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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 15

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Trace 9 (Physical mixture of Ofloxacin & Talc) shows combine features of each component but there are evident changes in onset. DSC RESULT-- COMPATIBLE 16

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DSC Study of Ascorbic acid p’ceutical formulations : 

Excipients: Sod. Crosscarmellose, MCC, Lactose Thermal stability was performed on ascorbic acid std. samples, binary mix. of ascorbic acid & excipients, under N2 & air atmospheres. IR & X-Ray Diffractometry: No chemical interaction However thermal stability of p’ceutical formulations are different. Temp. of beginning of thermal dregradation for Ascorbic acid is lowered of about 50C for MCC & 100C for Na-crosscarmellose & Lactose. Such facts must be considered for storage planning of tablets. (Ref: C.A. vol:146, No:25, June18,2007,507180t) 18 DSC Study of Ascorbic acid p’ceutical formulations

Limitations Of DSC : 

If thermal changes are very small, DSC can’t be used. DSC can not detect the incompatibilities which occur after long term storage. Eg. MCC / ASPIRIN… It is important to view results of such incompatibility testing with caution. Not applicable if test material exhibits properties that make data interpretation difficult. 19 Limitations Of DSC


DIFFERENTIAL THERMAL ANALYSIS Drug : Enalapril maleate (Ref:I.J.P.E.,Jan:2000,153) 20

Accelerated Stability Study : 

Accelerated Stability Study Different formulations of the same drug are prepared.(Eg. Enalapril maleate As above F1-F4) Samples are kept at 400C / 75 % RH. Chemical stability is assessed by analyzing the drug content at regular interval. Amt. of drug degraded is calculated. % Drug decomposed VS time(month) is plotted. 21

Diffuse Reflectance Spectroscopy: : 

Principle: In this technique solid drugs, excipients and their physical mixture are exposed to incident radiation. A portion of the incident radiation is partly absorbed and partly reflected in a diffuse manner. The diffuse reflectance depends on the a) Packing density of the solid b) Particle size c) Crystal form. 22 Diffuse Reflectance Spectroscopy:

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DRS is more useful than HPLC assay to detect surface discoloration due to oxidation or reaction with excipients. Lach & co-workers used this technique for detection of interaction between Isoniazid & LACTOSE in +ce of Mg-Stearate. 23

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24 CHROMATOGRAPHY A . SIC : SELF INTERACTIVE CHROMATOGRAPHY APPLICATIONS:- SIC is useful for protienous drug product & excipient EX :INF-Tau –New Anti-viral protein -Interaction studied with buffers. (note:buffers used to prevent aggregations) METHOD:- SIC is a modified type of affinity chromatography. Here,drug is made immobilized as the SP & soln. to be tested( excipient soln.) acts as MP. Measure Rt (Retention time) & compare with non –retained marker.

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25 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 :A: FIGURE:B: FIGURE:C: When interaction is repulsive,a sharper peak is obtained at a shorter retention time. When no net interaction between the immobilized drug,Rt=dead volume of column. When attractive interactions,it will have longer retention time& wider peak.

(B) TLC: Thin Layer Chromatography (C) HPTLC: High Performance Thin Layer Chromatography : 

TLC is generally used as confirmative test of compatibility after performing DSC. S.P. consist of powder (Silica, Alumina, Polyamide, Cellulose & Ion exchange resin) adhered onto glass, plastic or metal plate. Solution of Drug, Excipient & Drug: Excipient mixture are prepared & spotted on the same baseline at the end of plate. The plate is then placed upright in a closed chamber containing the solvent which constitutes the M.P. 26 (B) TLC: Thin Layer Chromatography (C) HPTLC: High Performance Thin Layer Chromatography

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No interaction 2spots having Rf value identical to those individual drug & excipient Interaction Complex formed will produce a spot having Rf value different from those of the individual components. 27


Chemical impurity profiles -Very important in influencing the long term chemical stability performance of the formulated drug product. Example (1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical excipients. POVIDONE Contains substantial conc. PEG 400 of HPOs with significant HPC batch to batch OR manufacturer POLYSORBATE 80 to manufacturer variations. While MCC, Lactose, High M.wt PEG, Polyxamer contains less amt. of HPOs. (Ref: J.Ph.Sci,vol:97,Jan:2007,106) 28 INCOMPATIBLE IMPURITIES

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(Ref: J.Ph.Sci.,vol:97,Jan:2007,106) 29 5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high HPO content.

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DCP – Sometimes, IRON may be present in DCP as impurities. It is incompatible with MECLIZINE HCl . (Fe NMT 0.04%) 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. 30

P- Glycoprotin inhibitor excipients : 

p-Glycoprotein is membrane associated transport protein. It is an efflux pump lies in tissue membranes. Some excipients have p-Glycoprotein efflux-pump inhibiting properties. EXAMPLES:- 1.PEG-32 lauric glycerides. 2.Polysorbate-80 3.PEG-50 Stearate 4.Polysorbate-20 5.Polysorbate-85 6.PEG-40 hydrogenated castor oil 7.PEG-35 castor oil (Ref: J.Ph.Sci.,vol:93,Nov:2004,2755) 31 P- Glycoprotin inhibitor excipients

Known Incompatibilities : 

Known Incompatibilities 32

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DECS in solid dosage forms : 

DECS in solid dosage forms Example 1:- Millard reaction:- is a non-enzymatic bimolecular browning reaction between reducing sugar and an amine. Mechanism:- 34

Stability study of Captopril tablets in Blister wrappers. : 

Stability study of Captopril tablets in Blister wrappers. Captopril Captopril disulfide Study evaluated Captopril tablets in blister wrapping made from moldable films of crystal clear PVC, Clear PVC/ Polyvinylidene dichloride, & Red PVC/ Polyvinylidene dichloride. Stored at 30 ± 20C & 75 ± 5% RH for 6 month. Content of Captopril & Captopril disulfide were detected by HPLC. Red PVC –Polyvinylidene dichloride packaging provide best barrier against moisture & gases in general. (Ref: C.A. vol:147, No:4,2007,79121t) 35 Example-2

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Example 3 Effect of Excipients on Hydrate formation in wet masses containing Theophylline During wet granulation Theophylline Shows Pseudopolymorphic changes that may alter its dissolution rate. Diluents Used: α- Lactose monohydrate Minimum water absorbing capacity. So not able to prevent but enhance Hydrate formation of Theophylline. Silicified MCC Highly water absorbing capacity. Able to inhibit the formation of Theophylline monohydrate at low moisture content. (Ref- J.Ph.Sci,vol:92,Jan:2003,516) 36

Drug excipient Compatibility Studies in Aerosols : 

Drug excipient Compatibility Studies in Aerosols Example 1:- Interaction of propellent-11 with aqueous drug products. Propellent 11 is trichloromonofluoromethane. HCl corrodes the Al-container. 37

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(Ref: J. Ph.Sci.,VOL:95,May:2006,1060) 38 Example 2: Beclomethasone- Hydroflouroalkane interactions: BDP is a Steroidal drug used in Asthma. Manipulation of above interaction: BDP particles coated with amphiphilic macromolecular excipient by Spray drying. Therefore, prevention of aggregation & production of physically stable suspension with excellent aerosolisation properties.

Drug Excipient Compatibility Studies in Parenteral products : 

Anti-oxidants 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 Break-down of Bi-sulphide Linkage in Insulin structure. Protamine- Insulin + Phenolic preservative tetragonal oblong crystals which is responsible for prolong action of insulin. 39 Drug Excipient Compatibility Studies in Parenteral products

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Surface active agents Polysorbate 80: One must concern about the residual peroxide present in Polysorbate. PS 80 Polyoxyethylene sorbitan ester of Oleic acid ( Unsatd.F.A) PS 20 Polyoxyethylene sorbitan ester of lauric acid ( Satd.F.A) So PS 20 is less prone to oxidation than PS 80. 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. 40

Effect of Rubber closure on haze state of Ceftriaxone Na for inj. : 

Effect of Rubber closure on haze state of Ceftriaxone Na for inj. Migration of Volatile components in the headspace of glass vials from rubber closure is potential source of haze formation in reconstituted soln of powders for parenteral administration. Head-sapce method was used to extract Volatile substance from diff. types of rubber closures used in Ceftriaxone Na for inj. Whose clarity were poor. The extract obt. were analyzed by GC-MS. (Ref: C.A. vol:146, No:17,April 23 :2007,343961v) 41


Encyclopedia of Pharmaceutical Technology,(vol-19) Pharmaceutical Dosage forms By Leon Lachman & Liberman Hand book of Pharmaceutical Excipients Hand book of Pharmaceutical Granulation Technology,Vol-81 Remington’s Pharmaceutical Science,21st edition,2005. Ansel’s pharmaceutical dosages form and drug delivery system ,VIII edition. Modern Pharmaceutics by Banker & Rhodes,4th edition,2002. Theory and Practice of Industrial Pharmacy by Lachman & Lieberman. 42 REFERENCES


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-94, Oct-2005, 2568. J. Ph. Sci., Vol-93, Jan-2004,132 J. Ph. Sci., Vol-93, Nov-2004, 2755. J. Ph. Sci., Vol-92, May-2003, 516. J. Ph. Sci., Vol-88, July-1999, 696. C.A. vol:147, No:4, July 23 :2007 C.A. vol:146, No:17,April 23 :2007,343961v C.A. vol:146, No:25,June 18 :2007,507180t C.A. vol:147, No:4, July 23 :2007,79121 43 REFERENCES


44 STUDY QUESTIONS:- 1.Enlist the techniques employed in studying drug-excipient compatibility study. How is Accelerated stability study carried out? (sept:2006) 2.Excipients can affect absorption &bio- availability :Justify the sentence. (sept:2006) 3.A Pharmacist want to develop SGC formulation of a new drug. What tests he should carry out in order to ascertain drug-adjuvant interaction? Give brief outline & the significance if each test. (sept:2004) 4.Enlist the technique employed in DE compatibility screening &detail about accelerated storage testing. Write a note on D.E.interaction in parenterals. 5.comments:- A) Drug-itself is taken as a sample in DECS. B) DSC is one of the important method to study DECS though not the complete one.

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