Compatibility study.

+8

No comments posted yet

Comments

Slide 1

Compatibility of Drug with Excipients and methods used to evaluate incompatibility. By:- Rinkal J. Patel II-M.Pharm Department of Pharmaceutics K.L.E.’s College of Pharmacy,Hubli-31. Evaluation seminar

Slide 2

content Introduction. Why compatibility study? Objectives of compatibility study. Types of incompatibility. Methods to detect incompatibility. Thermal methods. Non-Thermal methods. Examples for the interpretation of incompatibility from DSC curve.(Glipizide with tablet excipients)

Slide 3

Introduction The successful formulation of a stable and effective solid dosage form depends on selection of the excipients More suitable or easier administration, Patient compliance, Promote release and bioavailability of the drug and protection from degradation.

Slide 4

Before deciding the final formulation we must have readily available knowledge of potential physical and chemical interactions between drugs and excipients. which might affect chemical nature, stability, solubility and in vivo absorption of drugs.

Slide 5

Why compatibility tests? Identification of compatible excipients for a suitable formulation. 2. Identification of stable storage condition for drug in solid or liquid state.

Slide 6

Objective of Compatibility study The objective of the drug excipient compatibility studies is to identify as quickly as possible, the real and possible interaction between potential formulation excipients and the API. This is an important risk reduction exercise early in formulation development.

Slide 7

Types of incompatibility Physical:- The original physical properties , including appearance palatability, uniformity , dissolution characteristics are changed. 2. Chemical:- Deviation of chemical nature of active ingredient, its chemical integrity and labeled potency from the specified limits. 3. Therapeutic:- Therapeutic effect of active ingredient is changed .

Slide 8

Sample preparation a. Prepare mixture of drug & excipient, Place it in vial, place rubber closure and seal it. b. Same as above with 5% moisture in it. c. Pure drug for solid stability study. All samples of drug excipients are kept for 1-3 weeks at suitable conditions. Then sample is physically observed. Then analysed by thermal and non thermal methods. Degradation products are identified by mass spectroscopy, nuclear magnetic resonance or other suitable technique .

Slide 9

Methods to detect incompatibility. Thermal methods:- Thermal analysis is the measurement of how specific physical or chemical properties of a substance changes with temperature. The early forms of thermal analysis were based mostly on Thermal Gravimetric Analysis where the change in weight of a substance with temperature was measured.

Slide 10

The more important generally accepted thermal analytical techniques are listed as follows. Thermo-Gravimetric Analysis (TGA). Differential Thermal Analysis (DTA). Differential Scanning Calorimetry (DSC). Dielectric Thermal Analysis (DTA). Differential Mechanical Thermal Analysis (DMTA).

Slide 11

The majorly used two methods (DTA and DSC) are defined as followed: Differential thermal analysis (DTA):- Thermal analysis using a reference. The sample and the reference material (sample) are heated in one furnace. The difference of the sample temperature and the reference material temperature is recorded during programmed heating and cooling cycles.

Slide 12

Differential Scanning Calorimetry:-(DSC) measures the change of the difference in the heat flow rate to the material (sample) and to a reference material while they are subjected to a controlled temperature program. Like differential thermal analysis (DTA), differential scanning calorimetry(DSC) is also an alternative technique for determining the temperatures of the phase transitions like melting point, solidification onset, re-crystallization onset, evaporation temperature etc.

Slide 13

Differential scanning calorimeter (DSC) has been proposed as a rapid method for evaluating the drug–excipient interaction. Though it has certain advantages, such as requirement of small sample size and fast results, there are certain limitations also. This is because of exposure of drug–excipient mixture to high temperatures (up to 300 ◦C or more), which, in real situations, is not experienced by the dosage form. Therefore, the DSC results should be interpreted carefully, as the conclusions based on the DSC results alone can be often misleading and inconclusive.

Slide 14

Limitation 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 e.g Aspirin-MCC. It is important to view results of such incompatibility testing with caution. Not applicable if test material exhibits properties that make data interpretation difficult .

Slide 15

Use and Methodology DSC is a widely used to investigate and predict any physicochemical interaction between drug and excipients involving thermal changes. Method- the preformulation screening of drug excipient interaction require (1:1) Drug : excipient ratio, to maximize the interaction. Mixture should be examined under nitrogen to eliminate oxidative and pyrrolytic effects at heating rate (2.5 or 10OC/min) on DSC apparatus.

Slide 16

How to detect interaction by DSC Appearance of new peak Change in peak shape Melting point or peak temp. Onset of peak Elimination of endothermik peak Area of peak

Slide 17

Temperature Heat flow 1 3 2 1=Ofloxacine 2=Lactose 3=Ofloxacine:Lactose(1:1) 278.33 Absence of peak at 278.33O C.

Slide 18

Early Onset of peak 1 4 5 4=Starch 5=Ofloxacine:Starch(1:1) 278.33 Temperature Heat flow

Slide 19

IST For preparation of samples for IST, drug and different excipients were weighed directly in 4ml glass vials. After mixing on a vortex mixer for 2 min, 10% (w/w) water was added in each of the vials, subsequent to which the drug excipient blend was further mixed with a glass capillary. To prevent any loss of material, capillary (both the ends of which were heat sealed) was broken and left inside the vial.

Slide 20

The vials, after sealing with a teflon-lined screw cap, were stored at 50 ◦C (Hot air oven). Drug–excipient blends without added water and stored in refrigerator served as controls. The drug–excipient blends were periodically examined for any unusual color change. Samples were quantitatively analyzed using HPLC after 3 weeks of storage at above conditions. The sample preparation involved addition of 2ml of mobile phase in each of the vials.

Slide 21

The mixture was vortexed and transferred to 100 ml volumetric flask. All the vials were rinsed twice with the mobile phase and the volume made up. The samples were centrifuged and the supernatant filtered through nylon membrane filters (0.45 m pore size). After appropriate dilutions, samples were analyzed using HPLC and drug content determined from the calibration curve prepared within the expected range.

Slide 22

Non-Thermal Methods FTIR-Fourier Transform infrared spectrometry. TLC- Thin Layer Chromatography.

Slide 23

FTIR- Fourier Transform infrared spectrometry was developed in order to overcome the limitations encountered with dispersive instruments. A method for measuring all of the infrared frequencies simultaneously, rather than individually, was needed. The interferometer produces a unique type of signals which has all of the IR frequencies “encoded” into it. The signal can be measured very quickly usually on the order of one second. Thus the time element per second is reduced to a matter of a matter of a few seconds.

Slide 24

Examples for the interpretation of incompatibility from DSC curve.(Glipizide with tablet excipients)

Slide 25

FTIR spectra of Glipizide

Slide 26

This shows little change in thermogram of Glipizide:MCC(1:5) mixture as compare with pure Glipizide and hence Glipizide is compatible with MCC. Thermogram of Glipizide and MCC and their mixture.

Slide 27

This shows no change in thermogram of Glipizide:Lactose(1:5) mixture as compare with pure Glipizide and hence Glipizide is incompatible with Lactose. Thermogram of Glipizide and Lactose and their mixture.

Slide 28

This shows no change in thermogram of Glipizide:Mannitol(1:5) mixture as compare with pure Glipizide and hence Glipizide is compatible with Mannitol. Thermogram of Glipizide and Mannitol and their mixture.

Slide 29

This shows no change in thermogram of Glipizide:NaCl(1:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with NaCl. Thermogram of Glipizide and NaCl and their mixture.

Slide 30

Thermogram of Glipizide and Meglumine and their mixture. This shows no change in thermogram of Glipizide:Meglumine(1:1) mixture as compare with pure Glipizide and hence Glipizide is incompatible with Meglumine.

Slide 31

This shows no change in thermogram of Glipizide:CSD(4:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with CSD. Thermogram of Glipizide and CSD and their mixture.

Slide 32

This shows no change in thermogram of Glipizide:Talc(4:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with Talc. Thermogram of Glipizide and Talc and their mixture.

Slide 33

Thermogram of Glipizide and PVP and their mixture. This shows little change in thermogram of Glipizide:PVP(1:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with PVP.

Slide 34

This shows no change in thermogram of Glipizide:Magnesium stearate(1:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with Magnesium stearate. Thermogram of Glipizide and MgS and their mixture.

Slide 35

This shows no change in thermogram of Glipizide:HPMC(1:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with HPMC. Thermogram of Glipizide and HPMC and their mixture.

Slide 36

This shows no change in thermogram of Glipizide:Cellulose Acetate(1:1) mixture as compare with pure Glipizide and hence Glipizide is compatible with Cellulose Acetate. Thermogram of Glipizide and CA and their mixture.

Slide 37

Reference. Introduction to Fourier Transform Infrared Spectrometry by Thermo Nicolet. Journal of thermal analysis. Handbook onThermal Analysis by R. P. W. Scott. Selection of excipients for extended release formulations of glipizide through drug–excipient compatibility testing by Rajan K. Verma, Sanjay Garg; Journal of Pharmaceutical and Biomedical Analysis 38 (2005) 633–644. Compatibility study between ibuproxam and pharmaceutical excipients using differential scanning calorimetry, hot-stage microscopy and scanning electron microscopy ,P. Mura, et al, Journal of Pharmaceutical and Biomedical Analysis;18 (1998) 151–163.

Slide 38

Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets, Farnaz Monajjemzadeh a, et al, European Journal of Pharmaceutics and Biopharmaceutics ;73 (2009) 404–413. Drug-excipient interaction study of enalapril maleate using thermal analysis and scanning electron microscopy,M.L. Cotton, D.W. Wu and E.B. Vadas;International Journal of Pharmaceutics, 40 (1987) 129-142. Differential thermal analysis (DTA) and differential scanning calorimetry (DSC) as a method of material investigation; Grega Klančnik,RMZ – Materials and Geoenvironment, Vol. 57, No. 1, pp. 127–142, 2010. Compatibility study between chlorpropamide and excipients in their physical mixtures Fátima Duarte Freire; Journal of Thermal Analysis and Calorimetry, 97(1)July, 2009.

Slide 39

Thank you all

Summary: Compatibility of drugs with tablet excipients by thermal and non thermal methods.

URL: