A Seminar On Prepared by :- PATEL PARTH M.Pharm QA( Sem : II) Enrollment no:112070804010APMC COLLEGE OF PHARMACY 1 HIMMATNAGAR
INTRODUCTION :-Solid oral dosage forms are designed to deliver the drug through physiological mechanisms that preside throughout the gastrointestinal tract.Solid oral dosage forms provide a highly reproducible and convenient form of drug deliveryTo design an effective delivery system, it is important to know the physical state of the API in the dosage form. 2
The techniques include :Light microscopy,Polarized light microscopy (PLM),Scanning electron microscopy (SEM),Transmission microscopy,Fourier transform infrared (FTIR)Micro spectroscopy,Nuclear magnetic resonance (NMR) imaging,Near-infrared (NIR) analysis, andRaman spectroscopy. 3
Physicochemical characterization techniques :-Physicochemical characterization techniques are beginning to play a major role in the drug development process because they help us to understand the mechanism of drug delivery.An assessment of the internal structure of the dosage form and the micro homogeneity and morphology of the API in the dosage form can be made with the techniques that are discussed here. 4
Microscopy :-Light microscopy, PLM, SEM, and transmission microscopy are nondestructive techniques that can provide insight into the composition and homogeneity of the API throughout the dosage form.PLM and energy-dispersive X-ray spectroscopy (used in conjunction with SEM) are utilized to determine how an API is distributed within a granulation.Energy-dispersive X-ray spectroscopy, an elemental analysis technique, used to map chlorine content and reveal the distribution of the API in the granulation.These experiments demonstrate that the API exists as the hydrochloride salt in the granulation and retains its original particle size distribution; therefore, the high temperatures and drying conditions used in the manufacturing 6 process do not appear to have negatively affected the drug substance.
FIGURE 1 FIGURE 2Polarized light micrograph of Chlorine mapping of aa granulation. Crystals of the granulation containing aAPI (see arrow) are visible hydrochloride salt API.within the matrix of thegranulation. 7
X-Ray Powder Diffraction :-The molecules in a crystalline compound are ordered in a three-dimensional array called a lattice.When a collimated beam of X-rays is incident upon this lattice, X-rays are diffracted.Every crystal form of a compound produces its own characteristic X-ray diffraction pattern.This technique is useful for distinguishing between solid-state forms of a bulk drug substance and for characterizing changes in the solid state (e.g., distinguishing between polymorphs, hydrates, and solvates and characterizing phase transitions between them).The technique is useful for characterizing changes in the drug substance in a 8 solid state as it exists in a matrix of a formulation—for example, a change from a crystalline to an amorphous form or hydration, dehydration, etc.
To confirm that polymorphic form of the API does not change during the manufacturing process, an experiment was done utilizing X-ray powder diffraction patterns of crushed tablets, crushed placebo tablets and three lots of API were acquired. FIGURE 3X-ray powder diffraction patterns of crushed tablets (pattern 1), crushed placebo tablets (pattern 2), and three lots of the API (patterns 3-5). 9
As seen in the diffraction patterns, the crystal structure of the API remained unchanged during processing. This study revealed no obvious evidence of polymorphic changes of the API due to the manufacturing process.Thermal analysis :- Simultaneous thermo gravimetric and differential thermal analysis (TGA/DTA) is a useful technique for the solid-state characterization of pharmaceutical materials. Such characterization includes the determinations of loss on drying, phase transition temperatures, thermal stability, and whether or not water is bound or unbound. TGA/DTA combines the measurement of a change in mass of a sample as a function of temperature (TGA) with the temperature difference of a sample 10 compared with an inert reference material as a function of temperature (DTA).
The TGA/DTA data are derived from the response of the sample to a heating program. In DTA the sample temperature remains constant throughout an endothermic transition, whereas the sample temperature increases during an exothermic transition.A TGA curve is simultaneously acquired, yielding the corresponding mass change curve. These dual pieces of information make interpretations more straightforward than interpretation with either technique alone.TGA/DTA was utilized to monitor changes in the crystal morphology and physical changes of a hydrated API in a granulation blend and in tablets compressed from the blend. 11
FT-IR Micro spectroscopy :- FTIR micro spectroscopy, equipped with an automated stage, is a nondestructive technique that can be utilized to analyze small samples and to chemically map locations by identifying components within the sample. When unidentified crystalline particles were found growing on tablets during a stability study, FTIR micro spectroscopy with a spectral resolution of about 5 µm was used to chemically analyze and identify the minute particles.NMR Spectroscopy :- NMR Imaging :- To understand the release of an API from controlled-release tablets containing HPMC, NMR imaging techniques were used to measure the relaxation times and self-diffusion coefficients (SDCs) of water across the 12 gel layer.
In this study, the SDC values were found to increase with increasing distance from the gel region to the core of the tablet.The SDC gradients (the change in SDC value over distance) were found to vary among HPMC tablets with different levels of polymer substitution.This type of in vitro NMR imaging experiment can provide important information to guide formulation optimization and aid in the design of drug products that deliver the desired in vivo release characteristics.FIGURE 4Self-diffusion coefficients ofwater across the gel layer ofan HPMC tabletafter 3 hours hydration. 13
In another study, NMR imaging with a modified flow-through dissolution apparatus was used to assess the swelling of HPMC tablets.The series of images reproduced to show the physical changes in HPMC tablets over time under static conditions.Determining the swelling behavior of the HPMC with this type of imaging may increase the understanding of the release of the API from the dosage form.This approach was successfully applied to the study of matrix-controlled- release tablets as well as osmotic-release tablets.NMR imaging techniques provide information about the nature of the physical processes involved in the disintegration and dissolution of the drug product. 14
FIGURE 5 NMR images of HPMC tablets within a flow-through dissolutionapparatus under static conditions at swelling times of 1, 5, 13, and 19 hours (a–d, respectively). The black center regions show where thetablet is dry, and the bright regions around the tablet show where the gel is swollen. 15
Solid-State NMR :-Solid-state NMR studies have been used to study the characteristics of an API in melt-extruded pellets.The purpose of the study was to determine whether the high temperatures at which the melt extrusion process was conducted caused physical changes in the drug substance, such as the formation of a different polymorph or a change in salt form. 16
Mass Spectrometry :-Recently, time-of-flight MS combined with secondary-ion monitoring (TOF-SIMS) has been reported to be a useful tool for characterizing and imaging the distribution of the components within a solid dosage form.This technique :- could be extremely important for assessing the controlled release properties of a solid oral dosage form. The homogeneity and quality of the manufacturing process could be determined. applied to the analysis of the surface of beads, tablets, and granulations, allowing the chemical composition of more than one layer to be evaluated. 17
NEAR INFRAREDANALYSIS :-There is intense interest in using NIR techniques in several major areas of pharmaceutical operations: clinical supply identification, incoming raw material identification, assay and content uniformity testing of finished products.The following sections describe qualitative and quantitative examples of validated NIR methods currently in use. 18
Qualitative NIR Analysis :-Verification of the Identity of Packaged Clinical Supplies :- An NIR spectroscopic method to identify pharmaceutically active and inactive (placebo) clinical dosage forms is recently developed. NIR analysis is particularly suited to the verification of the identity of packaged clinical supplies because of its nondestructive nature, speed, and low cost. The method was developed to create and validate a one-time-use library of the spectra of clinical dosage forms prepared for double- blind clinical trials. 19
FIGURE 6NIR spectra of known active and placebo (inactive) products packaged intoblister cards. 20
Raw Material Identification :- Use of the technique for raw material identification is done for preparing the library which is composed of spectra from dozens of lots that are averaged into a single spectrum for each raw material. The spectrum of an unknown material is matched against all possible similar compounds. The unknown is either accepted or rejected based upon how close (within accepted variations) its spectrum matches that of a known compound.Blend Homogeneity :- The homogeneity of pharmaceutical raw materials during blending was followed by visual matching, spectral matching, or principal component 21 analysis of the spectra after discrete time intervals.
NIR spectra obtained after different mixing intervals were used to assess the extent to which four components were blended in a V-blender.NIR reflectance spectra were collected with the use of a fiber-optic probe at ―high,‖ ―middle,‖ and ―low‖ positions on the blender at 1, 5, 10, 15, and 20-minute intervals. Spectra of the four-component blend after 1 minute and 20 minutes of mixing are illustrated in Figures 13 and 14 respectively.This experiment shows the feasibility of using NIR to determine the blend homogeneity of both API and excipients simultaneously in real time, thus ensuring optimal content uniformity during compression or capsule filling.Spectra of four component blend after 1 minute and 20 minutes of mixing are illustrated in figure. 22
FIGURE 7NIR spectra at high, middle, and low positions of a V-blender after 1 minute of mixing. 23
FIGURE 8NIR spectra at high, middle, and low positions of a V-blender after 20 minutes ofmixing. 24
At each interval, the relative standard deviation (RSD) of the NIR results at a wavelength specific to the active component was calculated.In addition, parallel HPLC analysis of the blend was performed. To show that the NIR method is comparable to results obtained by analysis by HPLC, the RSDs of the NIR results and the RSDs obtained from the HPLC assay results were plotted versus minutes mixed.This experiment shows the feasibility of using NIR to determine the blend homogeneity of both API and excipients simultaneously in real time, thus ensuring optimal content uniformity during compression or capsule filling. 25
Recent scenario :-X-ray diffraction method and thermal analytical method, both technique were used by Macaroni E., et al. for structural characterization of two benfluorex hydrochloride polymorphs.Raman spectroscopic technique was used by Henson M.J., et al. to analyze the low concentration (0.5 % w/w) of API. The domain sizes and spatial distribution of API and major excipient are obtained.Thermal analysis was performed by Pfeiffer S., et al. for the process of characterization and identification of different crystalline forms and its thermodynamic relationship.New perspectives of 19F MAS NMR was used by Jiri B., et al. in the characterization of amorphous forms of atorvastatins in dosage 26 formulations.
FT-Raman spectroscopic technique was used by Skorda D., et al. for identification and quantitative determination of atorvastatin calcium polymorph in tablet. FT-Raman spectroscopic method was used by Sylwester M., et al. for quantitative determination of captopril and prednisolone in tablets.FT-IR technique was performed by Andrewchan K.L., et al. for spectroscopic imaging of a solid dispersion of nifedipine in PEG which is valuable in optimization in manufacturing of formulations.Near infrared technique was used by Hua Ma, et al. for characterization of powder blends. NIR technique was used by Weiyong Li, et al. as qualitative method for monitoring of nucleation and granule growth in fluid bed wet granulation. NIR technique was used by Weiyong Li, et al. for determination of polymorph conversion of an API in wet granulation using NIR calibration 27 models generated fron the premix blends.
Different types of solid oral dosage form:- Capsules • Hard Gelatine Capsules • Soft Gelatine Capsules • Modified-release Capsules • Enteric Capsules Tests • Content of active ingredients. • Determine the amount of active ingredient(s) by the method described in the Assay and calculate the amount of active 28 ingredient(s) per tablet.
The result lies within the range for the content of active ingredient(s) stated in the monograph. This range is based on the requirement that 20 tablets, or such other number as maybe indicated in the monograph, are used in the Assay.Where 20 tablets cannot be obtained, a smaller number, which must not be less than 5, may be used, but to allow for sampling errors the tolerances are widened in accordance with Table 1.The requirements of Table 1 apply when the stated limits are between 90 and 110 per cent. For limits other than 90 to 110 percent, proportionately smaller or larger allowances should be made. 29
Table 1Weight of active ingredients in Subtract from each lower limit Add to the uppertablet for samples limit for of samples of 15 10 5 15 10 50.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8More than 0.12 g but less than 0.2 0.5 1.2 0.3 0.6 1.50.3 g0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0 30
Uniformity of content This test is applicable to tablets that contain 10 mg or less than 10 mg or less than 10 per cent w/w of active ingredient. For tablets containing more than one active ingredient carry out the test for each active ingredient that corresponds to the aforementioned conditions. The test is also applicable to coated tablets other than filmcoatedtablets, irrespective of their content of active substance(s). The test for Uniformity of content should be carried out only after the content of active ingredient(s) in a pooled sample of the tablets has been shown to be within accepted limits of the stated content. The test for Uniformity of content is not applicable to tablets containing 31 multivitamins and trace elements.
Tablets Film-coated tablets. Dispersible Tablets Effervescent Tablets Modified-release Tablets Enteric-coated Tablets Prolonged- release Tablets Soluble Tablets Tablets for Use in the Mouth 32
TestUncoated Tablets DisintegrationUse water as the liquid. Add a disc to each tube. Operate the apparatus for 15 minutes, unless otherwise stated in the individual monograph. Examine the state of the tablets.If the tablets fail to comply because of adherence to the discs, repeat the test on a further 6 tablets omitting the discs. The tablets comply with the test if all 6tablets have disintegrated.The test does not apply to chewable tablets. 33
Coated Tablets Disintegration For coated tablets other than film coated tablets.Use water as the liquid. Add a disc to each tube. Operate the apparatus for 60 minutes, unless otherwise stated in the individual monograph. Examine the state of the tablets.If any of the tablets has not disintegrated, repeat the test on a further6 tablets, replacing water with 0.1 M hydrochloric acid. The tablets comply with the test if all 6 tablets have disintegrated in the acid medium. 34
For film-coated tablets.Carry out the test described above but operate the apparatus for 30 minutes, unless otherwise stated in the individual monograph.If coated tablets fail to comply because of adherence to the discs, repeat the test on a further 6 tablets omitting the discs . The tablets comply with the test if all 6 tablets have disintegrated.The test does not apply to chewable tablets. 35
Dispersible Tablets DisintegrationDetermine at 24º to 26º and operate the apparatus for 3 minutes. Uniformity of dispersion.Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth dispersion is obtained which passes through a sieve screen with a nominal mesh aperture of 710 mm (sieve number 22). 36
Effervescent Tablets DisintegrationPlace one tablet in a 250-ml beaker containing water at 20º to 30º; numerous gas bubbles are evolved.When the evolution of gas around the tablet or its fragments has ceased the tablet shall have disintegrated, being either dissolved or dispersed in the water so that no agglomerates of particles remain.Repeat the operation on a further 5 tablets. The tablets comply with the test if each of the 6 tablets disintegrates in the manner prescribed within 5minutes, unless otherwise stated in the individual monograph. 37
Enteric-coated Tablets DisintegrationIf the tablet has a soluble external coating, immerse the basket in water at room temperature for 5 minutes.Suspend the assembly in the beaker containing 0.1 M hydrochloric acid and operate without the discs for 120minutes, unless otherwise stated in the individual monograph.Remove the assembly from the liquid. No tablet shows signs of cracks that would allow the escape of the contents of disintegration, apart from fragments of coating.Replace the liquid in the beaker with mixed phosphate buffer pH 6.8, add a disc to each tube and operate the apparatus for a further 60minutes. Remove 38 the assembly from the liquid. The tablets pass the test if all six have disintegrated.
Soluble Tablets Disintegration Soluble tablets disintegrate within 3 minutes. The test is carried out using water at 15º to 25º. 39
References :-Ahuja S , Scypinski S , Separation and science technology A reference series vol-3 Handbook of modern pharmaceutical analysis, academic press, p.235-252pharmacopeal dosage forms:Tablets,edited by Herbert A. Liberman,Leon Lachman and Joseph.B.Schwartz , 2nd edition,Vol-2,Page No.318 to 337Indian pharmacopeia – 2007, Volume – 2, page no.633 – 634 and 662-665 . 40