Quantitation of Ink Transferred During Pharmaceutical Printing Operations Using Inductively Coupled Plasma Atomic Emission Spectroscopy

The identification of solid dosage forms is often achieved through printing with a non-toxic ink. Due to product purity requirements, a method to quantify the amount of ink applied to tablets and capsules is of interest to the pharmaceutical industry.

The following presentation investigated the use of inductively coupled plasma atomic emission spectroscopy (ICP-AES) as a direct method of quantifying the amount of ink on a tablet. Because the ink used contained an iron oxide pigment of known composition, quantitation of the iron content could be used to measure the amount of ink transferred to the tablet.

The quantitative results obtained using ICP-AES were in agreement with calculated values for the volume of ink in the gravure roll. Tablets exposed to “double printing” were easily detected by the ICP-AES method.     

Experimental Design for a Granulation Process with “Priori” Criterias

Optimization techniques representr analytical tools available for the best solution to a particular problem.

Pharmaceutical product and process design problems were structured as constrained optimization problems and subsequently solved by the “a priori” optimality approach using an exchange algorithm.

The effect of the amount of added water plus granulation time and impeller speed on two properties of the granulates were investigated.

Experimental results obtained for the optimal formulation agreed well with the predictions.     

A study on in vitro release of five brands of phenytoin capsules, marketed in iran

In relation to the new pharmaceutical system in Iran, the in vitro release of five brands of 100 mg phenytoin sodium capsules, namely A,B,C,D & E were determined in distilled water. using three dissolution methods, i.e. Rotating basket, Magnetic basket and Levy beaker method. Also the average amount of phenytoin content of each brand was measured.

The results showed that although the dissolution rate of each product is different by each method, but the pattern of drug release is more or less similar.

The dissolution time for products C and D is much longer than those of products A,B & C with all methods, but the dissolution behaviour of capsules C & D is not equivalent to those of standard “slow release” phenytoin capsules. The release pattern of products A & E are similar to those of standard “fast release” phenytoin capsules. The dissolution of product B is poor and not acceptable.     

Investigation on Process Parameters Involved in Polylactide-Co-Glycolide Microspheres Preparation

Indomethacin loaded polylactide-co-glycolide (PLGA) microspheres were prepared by emulsification solvent evaporation. The preparation involves several process parameters that can affect the morphological characteristics, the “in vitro” and “in vivo” dissolution behaviour of microspheres.

The evaluation of three process parameters, emulsification stirring rate, emulsifier concentration and dispersed phase to continuous phase ratio was carried out in order to correlate them to some microsphere properties.

Results show that the variables evaluated affect mainly microspheres drug content and, at less extent, particle size.     

Micromeritic Properties of Nitrofurantoin Microcapsules

In our previous study, we have prepared nitrofurantoin microcapsules using carboxymethylcellulose (CMC) and aluminium sulphate by a coacervation technique. In the present study, the micromeritics of these microcapsules were investigated in terms of standardization of the crude materials employed, the microcapsules product and the dosage forms prepared from these microcapsules. The microcapsules were prepared with a 1:1 core: wall ratio and sieved into three particle sizes. Both the micromeritic properties of the pure drug and the polymer were studied by determining their bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity, The particle size range went from approximately 250μm to 3000μm with a peak between 900μm and 1350μm. The results indicate that the flowability and the particle size of the resultant microcapsules were much increased compared with the raw materials. As the microcapsule size increases the porosity also increases but the density decreases.

The weight deviation of the microcapsules first sieved then filled into hard gelatin capsules was carried on according to the USP XXII. Hard gelatin capsule size was found by Lindenwald-Tawashi nomogram as number 3. The geometric mean diameters and the geometric standard deviation of microcapsules were calculated as 750 pm for number distribution and 1275μm for weight distribution and 1.52 for number and weight distribution respectively.

In addition to evaluate whether some kind of glidant will be needed during tableting of microcapsules and filling of them into hard gelatines, “Hausner ratio and consolidation indexes” were calculated.

The results obtained suggest that sustained release dosage forms of nitrofirantoin can be prepared from the obtained microcapsules as far as the micromeritic properties is concerned and the microencapsulation changed the micromeritic properties of the crude materials significantly.     

Good pharmaceutical manufacturing practices

In order to assure the quality of medicines and to encourage the implementation of the international system for the certification of the quality of pharmaceuticals, it was deemed necessary to specify the conditions under which pharmaceutical establishments should operate to provide full assurance that their products are safe for public health.

The French Government Order of 1. October. 1985 therefore provides for the establishement of new recommendations on good pharmaceutical manufacturing practices: “Bonnes Pratiques de Fabrication et de Production Pharmaceutiques: BPF 1985”.

Within the system of quality assurance, good pharmaceutical manufacturing practices represent that part which is concerned with manufacture.

Their implementation requires that the specification of the raw materials and packaging materials, the manufacturing and packaging processes and the control methods be defined and written beforehand, that the premises and equipment be adapted to the intended uses and that the staff have received appropriate training.

Good pharmaceutical manufacturing practices directly concern production departments and packing area, control laboratories, storage areas, purchasing departments, departments receiving raw materials and dispatching finished products. They also concern departments issuing instructions and written or computerised documents intended for the departments previously mentioned.

Although the collection of recommendations thus published constitutes a detailed document, the possibility of there being different methods for attaining the same objective is recognised.     

Dissolution Study of Prolonged Release Morphine Tablets Using Hydrophilic Matrices

This study presents the results of “in vitro” dissolution of prolonged release morphine tablets using hydroxypropylmethylcellulose. Tablets with four different doses were elaborated and the liberation from these formulated tablets was compared with that of the only commercial pharmaceutical preparation of this type registered in the Spanish Pharmaceutical Market.

The results of the dissolution tests show that the drug was gradually released in all cases and tablets had released from 60 to 90% of its contents after 8 hours.

In the comparative study, the commercial tablets showed the fastest release. In both cases the release rate was lower when artificial intestinal fluids were used as the dissolution medium.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Comparison of Methods for Evaluation of Flow Properties of Powders and Granulates

Powder mixtures and granulates with bulk densities ranging from 0.35-0.89 g.ml^-1 were tested regarding flow properties using the following methods: the Hausner ratio (packed bulk density/loose bulk density), rate of packing on tamping, flow rate through a 30 mm orifice, orifice diameter allowing free flow, and “drained” angle of repose.

The Hausner ratio and the angle of repose could be measured with a relative standard deviation of about 2 %. The orifice diameter could also be determined accurately and these three methods correlated well with each other.

The flow rate could only be measured on free flowing materials and the packing rate correlated poorly with the other methods.     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

The Use of Fractal Geometry in Pharmaceutical Systems

The nature of surface irregularity affects many phenomena including adsorption/desorption, catalysis, crystal growth, drug dissolution and chromatography. Many excellent models have been developed with the oversimplified assumption that all particles are smooth spheres; fractal geometry allows these models to be expanded to irregular surfaces by providing a quantitative means of assessing surface roughness.

An overview of fractal analysis is presented in the following, and the state of the art, as far as pharmaceutical systems are concerned are outlined. Erroneous approaches, as well as the directions pharmaceutical research and technology might take in the area of fractal analysis are suggested.

From a historical perspective, micromeritics (the science of particle size, shape and surface area) were first developed with the assumptions that all particles were smooth spheres.

Much excellent work has been developed with such an oversimplified model. For example, numerous workers have shown that particle flow through an orifice is a function of “particle diameter”, and experiments have most often been carried out on particles as close to spherical as possible, and as monodisperse as possible.

The science of micromeritics, the science of small particles, is the making of Dalla Valle (1943) who coined the term in a book of the same name which describes methods of particle size measurement, mostly used by soil scientists.¹     

Controlled Release from Glycerol Palmito-Stearate Matrices Prepared by Dry-Heat Granulation and Compression at Elevated Temperature

Diprophylline release from glycerol palmito-stearate “precirol” matrices containing different direct compression (DC) excipients, with variable dissolving/disintegrating ability, is investigated. The matrices are formed by employing dry-heat granulation and compression at elevated temperature.

Greater drug release prolongation is achieved with the dissolving DC excipients than with the swelling ones. The release is described on the basis of two biexponential first order models and the Weibull function as well.

The effect of compression conditions (temperature and pressure) on the drug release is found to be related to the compaction behaviour of the DC excipients, i.e. plastic deformation or fragmentation.     

Selecting Key Pharmaceutical Formulation Factors by Regression Analysis

The use of Selective Regression Analysis to determine which formulation factors are governing product properties is demonstrated. The techniques of using and combining the two procedures called “All Possible Regression” (APR) and “Stepwise Regression” (SWR) are presented and applied to a multivariate pharmaceutical formulation problem.

The technique was successfully applied to a system consisting of 10 response variables (tablet properties). Analysis of the results showed that for this formulation compression pressure and lubricant level exert the greatest effect on the majority of the properties. The results obtained from this method of analysis can aid the formulator in selectively controlling the product properties of choice while leaving the others undisturbed. Selective Regression Analysis also provides a basis for understanding the underlying mechanism of the system under consideration.     

Quality assurance and staff training

“G.M.P. Trends” is an american magazine publishing extracts of inspection reports: It is an official statement of errors, faults, omissions observed in the US pharmaceutical industry as regard good manufacturing pratices. A comparison between the “G.M.P. Trends” and the (“BPF”) “Bonnes Pratiques de Fabrication” (Good manufacturing pratices) points out the errors, defects or omissions observed and thus enable t o remodel staff training (1) (2).

Staff training is dealt with different chapters of the “BPF” staff, documents, samples, computerisation and risk generating product. Staff training is regarded as a mean for action: objectives, priority aims, choices and exchanges are to be defined.

We intend t o develop an example of answer to staff training needed in the pharmaceutical industry. The aim of this answer is the implementation of the good manufacturing pratices in a system which guarantees quality. This training is carried out within the framework of the directives and recommandations of the W.H.O. and U.N.I.D.O. with as a target the manufacturing of tablets of essential drugs.     

The use of optimazation techniques in pharmaceutical development

The lecture uses selected examples to illustrate the use of mathematical methods to optimize drug dosage forms:

Elucidation of compatibility between active ingredient and excipients required in the preformulation phase by factorial design.

Calculation of maximum allowable mean of particle sizes for active ingredient and the sum of auxiliary materials to achieve a sufficient content uniformity by applying the Stange-Pool equation.

Application of surface response research for identification of the working point in an “innocuous area of landscape” for scaling ups, handing over to production, of trouble shooting by using central composite desing and in the case of multiple constraints doing computerized grid search.

Only mentioned and not described in detail will be the methods for pharmacokinetical optimization, necessary for the development of modified release formulations.

Of course not for every development it is mandatory to use surface response research to get the necessary quality. But it is worthwile to apply refgularly factorial design for compatibility studies to calculate the necessary particle sizes and to compare in vivo results with dissolution rate data.     

The Effect of Hygroscopic Formulation Ingredients on the Sorption Characteristics of Tablets

In order to examine the effect of hygroscopic ingredients on the sorption characteristics of tablets, three hygroscopic additives - citric acid anhydrous (CAA), sorbitol (SI) and maltodextrin (MA) - were added at concentrations of 10% and 20% to a standard tablet granulate formulation prepared with three different initial moisture contents. The additives chosen were intended to be representative of a range of active ingredients with varying hygroscopicity characteristics.

The granulate/additive mixtures, together with the corresponding additive-free mixtures, were then tabletted, and the sorption isotherms of the resulting tablets were determined. The sorption-related changes in hardness, thickness, diameter and disintegration time were also investigated.

Examination of the sorption isotherms showed that the position of the “ansor-ption point” - the point where the isotherm crosses the x-axis and thus the point at which the tablets start to adsorb water - was much more dependent on the initial moisture content of the tablets than on the presence of a hygroscopic additive. The presence of a hygroscopic additive had little or no effect.

The additives did not begin to have any marked effects on the sorption isotherms of the finished tablets until the relative humidity level reached 62%. Above 62%, however, the differences in the hygroscopicity characteristics of the individual additives had a direct impact on the sorption profiles of the tablets.

As increasing amounts of moisture were adsorbed, tablet hardness fell whilst tablet thickness and diameter increased. The increases in thickness were in all cases greater than the increases in diameter. These findings applied to all tablets irrespective of their initial moisture content.

The sorption-related changes in disintegration time did not exhibit any consistent pattern and have therefore not been interpreted.

A comparison of the areas under the adsorption isotherms yielded the following results:

• The three additives adsorbed differently. Their adsorption, however, was always greater than that of any of the tablet variants.

• The areas under the adsorption isotherms of the additive-containing tablets were in all cases greater than the areas under the adsorption isotherms of the corresponding additive-free tablets. However, the differences were not always directly related to the concentration of the additive or to the area under the adsorption isotherm of that additive.

The relevance of these findings for routine pharmaceutical practice is discussed.     

Enhanced Solubility of Paracetamol by Various Hydrotropic Agents

The increase in the aqueous solubility of paracetamol by the use of various hydro tropes was studied.

These agents were sodium glycinate, sodium gentisate, sodium salicylate and nicotinamide. All of these agents increased the aqueous solubility to varying degrees, with nicotinamide and sodium salicylate being the most efficient solubilizers.

A conductance parameter was investigated as a mean of aiding interpretation of the solubility data. Dielectric constants could only be determined in the nicotinamide systems.

Ultra-violet spectral analysis, TLC, infra-red, and NMR techniques were utilized in order to elucidate the solubility mechanism. These tests indicate that no special bonding or complex formation exists for the sodium salt hydrotropes in these preliminary work. There is some evidence from UV & TLC analysis that nicotinamide and paracetamol enter into complex formation.

The other hydrotropic agents, in this study indicate the mechanism of solubilization is one of “salting - in” by causing miscibility of two formally immiscible liquid phases of ternary systems.     

Stability Indicating Hplc Method for Ribavirin and its Pharmaceutical Dosage Forms

The present work describes a specific, stability indicating HPLC method for determination of Ribavirin (1) and its pharmaceutical dosage forms.

Ribavirin was chromatographed on a microbondapak C18 column utilizing a simple mixture of 0.01M dibasic potassium phosphate and methanol (95: 5). The detection was done at 207 nm.

The available literature was scanned to locate the various methods(2,3) available along with the one reported in USP XXII.

A comparative study was made of the proposed method and USP method and the advantages over the USP method have been discussed.

The low value of Relative standard deviation and recovery of the drug in the range of 99.1% to 101.5% indicates a good precision and non-interference of the method.     

Applying GMP to Computerization in a Solid-Oral-Dosage-form-Factory

Quality Assurance and Pharmaceutical security as well must be given a particular consideration both for hardware and software when computerized pharmaceutical industrial operations are concerned

Hardware: The preparation of validation should begin with the design of a computerized system and rely upon specifications and upon defined operational limits

It is suitable to prepare documentation as from the development of the system in order to obtain a fruitful communication between all those concerned with design, implementation, maintenance, validation and auditing

A revalidation procedure should be prepared and maintained updated, in the event of a change in one or several operating conditions

Software: As with hardware, validation of software should be envisioned as early as the development phase. Preparation of test procedures and documentation should start at this very stage. Qualification and validation will be designed to find errors in the program and not to prove that no errors exist. They will be carried out at the operational boundaries of the software and will aim at testing the critical decision paths of the program. Verifications must be repeated a sufficient number of times to demonstrate that the results are repeatable

As with other pharmaceutical manufacturing systems, a formal procedure should exist to support changes made to the software. Vendor supplied software should be verified and documented with the same rigour and details that in-house developed software. Manual back-up systems must be provided for and regularly tested in the event of failure of the automated process. Computerized systems and good manufacturing practices applied to manufacturing of solid oral dosage forms: An application of the above-stated principles is given and illustrated     

ULTRA-PRECISION DIAMOND MACHINING OF ADVANCED TECHNOLOGY COMPONENTS

The design, development, and application of ultra-precision CNC machines for

the single point diamond turning of non-conventional metal optical components (Al, Ge, etc. )

the diamond grinding of ferrite and, other ceramic components for magnetic disc flying heads, etc.

is described. In both cases, tolerances on workpieces in the order of ± 0·1 μm were specified and achieved, together with the overriding need to minimize degenerated surface layers, i.e. surface damage.

The effects of chip formation at low depths of cut are discussed. The factors affecting the depths of “damaged layers” formed in turning and grinding are mentioned. Typical advanced technology components for which ultra-precision diamond turning or grinding are widely used are:

Convex mirrors for high output C0₂ laser resonators

X-ray mirrors

infrared lenses in germanium for thermal imaging systems

scanners for laser printers. and drums for copiers

elliptical mirrors for YAG laser beam collectors

spherical bearing surfaces in beryllium, copper, and other materials

ceramics for magnetic read/write heads for computer memory discs

ceramics for cams, cam followers, valve seat inserts, cylinder liners, bearings, cylinder heads, turbo impell ers, etc.

Both single point and diamond grinding for ultraprecision low stress surfaces demand high precision machines that provide

high stiffness of structures and high band-width servo drives;

low rumble, high averaging bearings such as hydrostatic air or oil;

high internal damping of stuctures and drive systems;

multi closed loop control of many parameters, including temperature of coolant and temperature gradients across structures and sub-systems;

coolant delivery to the abrasive/workpiece interface is of critical importance for controlling high surface finish and minimizing surface tresses.

The paper gives examples of how these problems are satisfied in today's state of the art ultra-precision CNC machine tools.