dear reader: Solubilization as a solution to the challenges facing the pharma industry

Transcription

1 Excipients & Actives for Pharma No. 27, 2012 CONTENTS dear reader: Solubilization as a solution to the challenges facing the pharma industry New names, new horizons: BASF's new dermatology and solubilization portfolios PAGES 2 3 Soluplus For improving solubility and bioavailability PAGES 4 7 Analytical investigation of solid dispersions PAGES 8 9 Trouble-shooting Solubilization and temperature, crucial parameters in dissolution testing PAGES Determining the minimum amount of Kollicoat Smartseal 30 D formulation to be applied for taste-masking functionality PAGES EXCiPACT TM A new, voluntary international pharmaceutical excipients cgmp and cgdp certifi cation scheme PAGES Ibuprofen DC 85 Production site transfer successfully completed PAGE 18 NEWS PAGES BREAKING NEWS PAGES CAlENDAR PAGE 24 PREVIEW PAGE 24 The pharmaceutical industry is currently facing significant challenges in new drug development: the drying pipeline of NCEs, cost pressure from the health authorities, the need to differentiate generic and OTC drugs on the market and stricter regulations for excipients on a global basis. Increasing the bioavailability of a drug molecule in an accepted dosage form is the toughest of these challenges. Increasing bioavailability by the solubilization of actives is an important approach to help to overcome this. In new drug development, the majority of the new chemical entities are lipophilic and/or have low permeability. Commonly, new actives fail during development due to these negative properties. At the same time, development cycles and costs are increasing. BASF can help here with know-how, products and services. Our rebranded portfolios of Kolliphor TM solubilizers and Kollisolv TM cosolvents offer the broadest toolbox of established excipients for solubilization in the industry. True to its legacy of innovation, BASF continues to develop new innovative solubilizers like Soluplus. Our SoluHTS screening robot helps you to screen and identify the most suitable solubilization excipients faster, helping to speed up development time. Our wide portfolio of solubilizers and services not only support the development of new drugs but also help to differentiate generic drugs. Due to the increasing cost pressure placed on me-too products, differentiation of secondgeneration generics is a key factor in the lifecycle management of drugs. Solubilization can be an important technology platform for this. Our expertise and products for innovative and cost-effective production technologies, such as hot-melt extrusion, spray drying and selfemulsifying systems, are an important approach to improving existing formulations and extending product life cycles. Bioavailability enhancement technologies are also the key to differentiating over-the-counter drugs for consumers. Claims such as faster action, fewer side effects, longer lasting effects or additional fortification with vitamins are facilitated by the use of solubilizers. One example is our Kolliphor TM TPGS, a vitamin E- based solubilizer which can increase the absorption of actives extremely effi ciently. Unfortunately, there is no single way out of the maze of pharmaceutical development. But luckily, BASF can help with its know-how, products and services for bioavailability enhancement, helping you to find the right path through this maze. And this all comes with quality you can trust. Yours sincerely, CONTACT PAGE 24 Dr. Ralf Fink Vice President of Global Marketing, Pharma Ingredients & Services

2 IN FOCUS: BRANDING HARMONIZATION New names, new horizons: BASF s new dermatology and solubilization portfolios Nina Karpynec PUBLISHER: BASF SE Pharma Ingredients & Services EDITORIAL STAFF: Ralf Fink Andres-Christian Orthofer Karl Kolter Jan Bebber AUTHORS: ABOUT US Christian Becker Claudia Easterbrook Florian Wildschek John Gianonne Kristina Bräunig Nigel Langley Matthias Karl Nina Karpynec Sofiya Yashchuk Thomas Rosen Thorsten Agnese Thorsten Cech Tony Scott Wendel Wohlleben BASF's new dermatology and solubilization portfolios are now better than ever offering an even wider range of innovative pharmaceutical-grade solubilizers, emulsifiers, solvents, consistency factors and emollients. To make these portfolios easier to navigate, we have developed a new naming system for our products. The new names are related to function in the formulation and compendial designations so customers can easily identify each excipient s application and chemical composition. All products within these portfolios now have Kolli as the first part of the brand name, plus a second part reflecting its function: phor for amphiphilic substances such as solubilizers and emulsifiers, solv for solvents, wax for consistency factors and cream for emollients. A link between monographic names or former names is made by a suffix. Increasing safety Since the 'Kolli' brands are used for pharmaceutical-grade excipients only, customers can directly associate the product line with pharmaceutical quality and all related services. This avoids mix-ups and ultimately increases patient safety. New names, same great quality The change in trade names in no way affects the quality of our products or our production processes. All affected products will continue to be manufactured to the same high standards at the same sites, with the same tried-and-tested QA systems in place. We have started selling the rebranded products under their new names from April 1st The adjustment process will be completed by the end of the year. CONCEPT/LAYOUT: Château Louis Strategische Markenführung und Kommunikation GmbH PRINT: johnen-druck GmbH & Co. KG Trademarks are owned by BASF SE New naming logic Page 2

3 Conversion table Don t know the new name of an excipient? No worries just enter the old name or the compendial designation into the fields on our homepage and our conversion table will do the rest: Excipients/Home.aspx New positioning for dermatology and solubilization portfolio The rebranding is also part of our repositioning of the new BASF excipient portfolio for dermatology and solubilization. Our new dermatology portfolio the perfect solution for every skin care challenge At BASF, our experts understand the many sides of dermatology the challenges of creating a stable, high-performance formulation while ensuring a pleasant and appealing look and feel. Our new and improved portfolio for topical applications goes above and beyond these requirements, delivering a host of value-added benefits to our customers. Whatever the excipient or active ingredient, BASF is the right partner for the dermatology industry. Our broad product range has had an extensive makeover, and now features exciting innovations such as improved topical delivery systems and milder excipients plus new names for our main lines. What s more, from emollients to APIs, our entire dermatology line meets the highest standards and all relevant regulatory requirements. Why choose BASF for your topicals challenges? Key industry partner, with a broad dermatological ingredients portfolio Extensive expertise and understanding of topical products Innovative breakthroughs such as improved delivery systems Meets the highest regulatory and quality requirements Our new solubilization portfolio opening new horizons in solubility and bioavailability At BASF, we understand that even the most promising active ingredient is of little use unless it can be effectively solubilized and made bioavailable. So we have designed our solubilization portfolio to meet the toughest challenges. Our extensive range of solubilizers, cosolvents and matrices for all common dosage forms including solids, liquids and semi-solids includes novel excipients particularly well-suited for poorly soluble drugs. Selecting the right solubilization product and technology for a poorly soluble API often involves much trial and error. But when you partner with our experts, you can tap into their extensive solubilization expertise and experience with all key technologies such as hot-melt extrusion, spray drying and drug layering. What s more, they have access to industryleading tools such as our high-throughput screening (HTS) robot putting them in an excellent position to help customers tackle their solubilization and bioavailability challenges rapidly and efficiently. Why partner with BASF? Broad portfolio for all common dosage forms Innovative excipients for poorly soluble APIs Proven performance and safety Experience with key technologies such as hot-melt extrusion "The new names are related to function in the formulation and compendial designations so customers can easily identify each excipient s application and chemical composition." Page 3

4 SolubiLization Soluplus For improving solubility and bioavailability Matthias Karl, Wendel Wohlleben and Karl Kolter IntroductION Numerous drugs, particularly those of the modern generation, are characterized by poor water solubility and low bioavailability [1, 2, 3]. This is one of the major problems in drug development. An appropriate technique for increasing solubility and bioavailability is the formation of solid solutions prepared by hot-melt extrusion [4]. According to the requirements of such formulations and processes, the new polymeric solubilizer, Soluplus, a graft copolymer composed of polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate, was developed. Here, the most important goal was to find a molecule capable of solubilizing poorly soluble actives while being easily extrudable. This was achieved by a unique structure with lipophilic and hydrophilic moieties, where the lipophilic ones strongly interact with the lipophilic poorly soluble actives and the hydrophilic ones provide the required water solubility. This new polymeric solubilizer outperforms many of the well-known low molecular weight surfactants and solubilizers and is easily applicable to solid oral dosage forms. The low hygroscopicity and glass transition temperature (Tg of 70 C) set it apart from other molecules used as solubilizers [2]. FIGURE 1 CMC of Soluplus in demineralized water at 23 C Polymers and actives Polymers studied: Soluplus, Kolliphor TM RH 40 (Cremophor RH 40), Kolliphor TM HS 15 (Solutol HS 15), Kolliphor TM PS 80 (Polysorbate 80 PH) and Kolliphor TM P 407 (Lutrol F 127), all from BASF SE, Germany. APIs studied: estradiol, piroxicam, clotrimazole, carbamazepine (all Pfannenschmidt, Germany), griseofulvin, cinnarizine, itraconazole, danazol (all Selectchemie AG, Germany), ketoconazole and fenofibrate (Sigma Aldrich, Germany). FIGURE 2 Determination of the structure of Soluplus above the CMC by analytical ultracentrifugation. Page 4

5 Results and discussion Due to its bifunctional character, Soluplus is able to act as a matrix polymer for solid dispersions and is capable of solubilizing poorly soluble drugs in an aqueous solution., The critical micelle concentration (CMC) is usually considered an important prerequisite for solubilization, since micelles are formed only above this concentration. Thus, a low CMC indicates that a surfactant is highly amphiphilic and probably highly effective in solubilization. Soluplus forms micelles at a CMC of approx. 8 ppm in water, which is a lower value than that of various Kolliphor grades. The actual structure of the polymer was determined by analytical ultracentrifugation (AUC). Particle size distribution by AUC showed a bimodal distribution with 2 separate peaks, which can be attributed to single Soluplus molecules at approx. 3 to 4 nm, and the micelles of Soluplus at approx. 20 to 30 nm, composed of a larger number of molecules. The potential affinity between the polymer and a drug that is poorly soluble in water can be tested using various methods. The easiest approach is to determine the solubilization capacity of the polymer in aqueous solution. Using phosphate buffer as a solvent (e.g. ph 7.0) ensures that no ph shift occurs when testing ionic polymers or drugs. Thus, solubility effects due to ph shift can be avoided [5]. A 10% polymer/solubilizer solution in phosphate buffer is saturated with the API and stirred for 72 h at room temperature. The resulting suspension is filtered through 0.45 µm filter and the content of solubilized API determined in the filtrate by UV spectroscopy [5]. FIGURE 3 Results of solubility enhancement of different solubilizers for various water-insoluble drugs. In four model drugs out of the ten studied, Soluplus outperformed the other solubilizers. This clearly demonstrates that Soluplus is capable of solubilizing water-insoluble drugs. The solubilizing potential of Soluplus, Kolliphor RH 40, Kolliphor HS 15, Kolliphor PS 80 and Kolliphor P 407 were tested. Estradiol, piroxicam, clotrimazole, carbamazepine, griseofulvin, ketoconazole, cinnarizine, fenofibrate, itraconazole and danazol were used as poorly soluble model drugs. As already indicated above, increasing dissolution rates and bioavailability of poorly soluble APIs in water are important challenges in dosage form development, and the formation of a solid solution can solve them. The polymer dissolves the drug in the solid state, and when it is dissolving in the gastrointestinal tract it transfers the drug to an aqueous environment at a high concentration. Thus, oversaturated solutions are obtained an ideal prerequisite for enhanced bioavailability [5]. The solid solutions of itraconazole/soluplus and danazol/soluplus were prepared using a co-rotating twin-screw extruder PolyLab OS (ThermoFisher, Germany) with a screw diameter of 16 mm and a length-to-diameter ratio of 40D. The feed rate was 1 kg/h for itraconazole and 0.9 kg/h for danazol. The speed of the extruder screws was 200 rpm. The barrel temperature was 150 C for itraconazole and 140 C for danazol. The in-vitro drug release experiments were carried out without the addition of any further solubilizer in the dissolution medium 0.1 N HCl (non-sink conditions) in order to prove that there is sufficient dissolution and that there is no crystallization of drug [5]. Page 5

6 Itraconazole with Soluplus showed a strongly enhanced dissolution rate compared to the crystalline itraconazole (Figure 5). From these results it is obvious that this polymer is capable of solubilizing drugs effectively, not only in a solid state but also in an aqueous environment; it is also capable of preventing crystallization. extrudate Bioavailability cannot be tested in in-vitro experiments but only in in-vivo studies, both in animals or in humans. The in-vitro dissolution characteristics give some indication of the efficacy in humans but often there is no exact in-vitro in-vivo correlation. In order to prove the in-vivo effect of Soluplus, animal studies were performed. The solid solutions of itraconazole and danazol in Soluplus prepared by hot-melt extrusion were administered to beagle dogs, as were the APIs as crystalline compounds and as physical mixtures of API and Soluplus (Figures 6 and 7). FIGURE 4 Soluplus combines the benefi ts of a solid solution and solubilization the formulations were: 1. Crystalline API (95% API, 5% disintegrant) 2. A physical mixture of API and Soluplus (15% API, 80% Soluplus, 5% disintegrant) 3. A solid solution of API and Soluplus (95% solid solution (85% Soluplus and 15% API), 5% disintegrant). These figures reveal that itraconazole and danazol are poorly absorbed without special formulations. The crystalline drug and the physical mixture did not result in significant plasma levels of drug. In contrast, the solid solutions with Soluplus tremendously enhanced absorption, in the case of itraconazole by a factor of 25 and in the case of danazol by a factor of 15. FIGURE 5 Drug release of pelletized Soluplus/15% itraconazole extrudate (w/w %) compared to crystalline itraconazole, both containing 100 mg itraconazole Page 6

7 Conclusions Soluplus is characterized by an amphiphilic structure leading to micelle formation in water at very low concentrations. Soluplus is able to act as a matrix polymer for solid dispersions. It is capable of solubilizing insoluble drugs in aqueous solution and preventing crystallization. Soluplus in solid solutions significantly enhanced the bioavailability of poorly soluble API. Solid solution of itraconazole Crystalline itraconazole Physical mixture of itraconazole FIGURE 6 Blood concentration of itraconazole (dose: 10 mg/kg body weight itraconazole, capsule) administered to beagle dogs in various formulations REFERENCES [1] B. W. Müller. Solubilization of drugs with poor solubility, ExAct, No. 14 (pages 2-5) (2005). [2] H. Hardung, D. Djuric and S. Ali. Combining HME & solubilization: Soluplus - the solid solution, Drug Delivery Technology, 10 (page 3) (April 2010). [3] M. Mehta. AAPS/FDA Workshop on Biopharmaceutics Classification Systems, (pages 25-27) (September 2002). Blood concentration [ ng/ml ] Solid solution of itraconazole Crystalline danazol Physical mixture of itraconazole [4] Crowley, M. M., et al. Pharmaceutical applications of hot-melt extrusion: Part 1. Drug Dev Ind Pharm, 33, (pages ) (2007). [5] K. Kolter, M. Karl, S. Nalawade, N. Rottmann. Hot-melt extrusion with BASF pharma polymers, BASF Extrusion Compendium (October 2010). FIGURE 7 Beagle dogs, dose: 30 mg/kg bw danazol Blood concentration of danazol (dose: 30 mg/kg body weight danazol, capsule) applied in beagle dogs in various formulations Time [ h ] Page 7

8 SolubiLization Analytical investigation of solid dispersions Matthias Karl and Karl Kolter IntroductION Melt techniques (e.g. hot-melt extrusion, spray congealing and melt granulation), solvent procedures (e.g. spray drying, solvent casting and freeze drying) and other technologies (e.g. milling) are different manufacturing methods for solid dispersions. The most prominent techniques are hot-melt extrusion and spray drying [1]. Investigation of formulations containing APIs is carried out using several methods, depending on the type of dosage form developed. The evaluation methods can be used to differentiate between solid dispersions (molecularly dispersed drug, without crystals), solid dispersions in which the drug is only partly molecularly dispersed (with crystals) and physical mixtures of drug and carrier [2]. It is difficult to precisely characterize systems which are molecularly dispersed from those that are not due to the complexity of the systems, and different analytical methods may yield contrasting results. In many instances, a combination of two or more methods is required to obtain the complete picture [3]. This article will specify three important analytical methods for characterizing solid dispersions: powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and in-vitro drug release. Analytical methods Different molecular structures (crystalline, amorphous and molecularly dissolved) of the drug in the matrix can be encountered in solid dispersions. The principle of XRD is based on Bragg s Law, in which parallel incident X-rays strike the crystal planes and are then diffracted at angles related to the spacing between the planes of the molecules in the lattice. Crystallinity is indicated by a characteristic fingerprint region in the diffraction pattern. If the fingerprints of drug and carrier are not superimposed, the crystallinity of the FIGURE 1 Lin (counts) XRD examples of amorphous and crystalline extrudates of Kollidon VA 64 with the API itraconazole compared to the pure and crystalline API drug and polymer following e.g. hot-melt extrusion can be determined (Figure 1). Thus, X-ray diffraction can be used to differentiate between solid dispersions in which the drug is amorphous and solid dispersions in which it is at least partly present in crystalline form, regardless of whether the carrier is amorphous or crystalline. However, the sensitivity of the XRD technique is limited and cannot generally detect crystallinity of less than 10% [3]. 2 - Theta scale - Amorphous system - Crystalline system - Itraconazole DSC analyzes the system as a function of temperature. This method has been widely used to study the thermal properties of materials used for example in hot-melt extrusion. DSC can be used for the determination of transitions (melting point (Tm), glass transition temperature (Tg)) coupled with endothermic and exothermic phase transformations. Generally, the hot-melt extrudate is scanned and compared to the results of the individual components. The lack of melting transition in the DSC scan of the hot-melt extrudate (Figure 2) indicates that the drug is present in an amorphous or molecularly dissolved state rather than in crystalline form (3). Page 8

9 1.0 - Soluplus /itraconazole extrudate ( slightly crystallized ) - Soluplus /itraconazole extrudate ( strongly crystallized ) - Soluplus /itraconazole extrudate ( non-crystallized I ) - Soluplus /itraconazole extrudate ( non-crystallized II ) Preview In our next edition of ExAct, we will present additional analytical techniques (e.g. infrared spectroscopy, Raman) for detecting crystallinity and characterizing solid dispersions. Heat flow [W/g] 0.5 Tg Tm 0.0 Temperature [ C] FIGURE 2 DSC examples of amorphous and crystalline extrudates of Soluplus with the API itraconazole Besides XRD and DSC, in-vitro drug dissolution is also relevant and is an important tool for studying solid dispersions. This is because it reveals whether the drug dissolves completely or not and whether the polymer prevents crystallization and keeps the drug in an oversaturated dissolved state under non-sink conditions [4]. Three different types of behavior of drugs formulated with water-soluble polymers can occur: The target profile is that the drug dissolves quickly and no recrystallization takes place. The second type is that the drug dissolves and recrystallization occurs later, leading to a decrease in the dissolution curve. And in the third type, crystallization occurs quickly and almost simultaneously with the dissolving of matrix polymer, leading to a very low and incomplete dissolution curve [4]. Drying temperature 70 C (vacuum) overnight / 20 bar cup These test methods can also be applied to check whether a formulation is stable after storage under various conditions. Crystallization can occur particularly when the drug has been incorporated above the saturation level, leading to change in its biopharmaceutical properties [5]. The in-vitro dissolution characteristics of a drug formulation in various dissolution test models (medium composition, volume, biomimetic fluids etc.) might be different and they provide a limited indication only of efficacy in humans. However, almost complete in-vitro dissolution combined with a high degree of supersaturation maintained over a longer period of time are essential prerequisites for a significant increase in bioavailability. This does not necessarily mean, of course, that the quickest dissolution always leads to the best bioavailability [4]. REFERENCES [1] T. Reintjes. Solubility enhancement with BASF Pharma Polymers, Solubilizer Compendium (October 2011). [2] P. H.-L. Tran, T. T.-D. Tran, J. Bom Park, B.-J. Lee. Controlled release systems containing solid dispersions: Strategies and mechanism, Pharmaceutical Research, 28 (page 10), (2011). [3] S. Singhal, V. K. Lohar, V. Arora. Hot melt extrusion technique, WebmedCentral Pharmaceutical Sciences, 2 (1): WMC (2011). [4] K. Kolter, M. Karl, S. Nalawade, N. Rottmann. Hot-melt extrusion with BASF pharma polymers, BASF Extrusion Compendium (October 2010). [5] W. L. Chiou, S. Riegelman. Review article: Pharmaceutical applications of solid dispersion systems, Journal of Pharmaceutical Sciences, 60 (page 9), (1971). Page 9

10 SolubiLization Trouble-shooting Solubilization and temperature, crucial parameters in dissolution testing Thorsten Agnese, Thorsten Cech, Florian Wildschek At present, the pharmaceutical industry is facing the problem that most of the recent APIs are of poor solubility and low bioavailability. A huge variety of technology approaches such as hot-melt extrusion are normally assessed for formulating these actives in such a way that the active can be administered to the human body. However, the pharmaceutical industry is not only facing new technologies. With new recent kinds of dosage forms, analytical aspects have to be considered that were of minor importance in the past. This article deals with one of these aspects the potential change of media temperature when taking samples during dissolution testing. Solubility [ mg / L ] y = x Problem What is the major difference between classical dissolution testing (the active is readily soluble in the dissolution medium) and the dissolution testing of poorly soluble APIs? FIGURE 1 Temperature [ C ] Solubility of carbamazepine in HCl (0.08 mol/l) as a function of medium temperature In general, the maximum amount of substance that can be dissolved in a medium is a function of temperature. Thus, the higher the temperature the more substance can be dissolved. However, in classical pharmaceutical applications of readily soluble actives, some milligrams of API have to be dissolved in e.g. 900 ml of dissolution medium. Here, temperature only affects the solubility kinetics (dissolution time), yet there is no limitation regarding saturation. Typically, the whole amount of active can be dissolved in the medium even at ambient temperatures. When talking about solubilization, the dissolution test inevitably leads to saturated or even oversaturated systems. These systems are strongly affected by temperature. Let s have a look at carbamazepine as an example of a poorly soluble active. It comes in dosage forms of 200, 300, 400 and 600 mg/dose, whereas all but 200 mg exceed the maximum solubility of the active in HCl (0.08 mol/l) at 37 C. How vital is temperature for reliable results? The dissolution vessel and the dissolution medium respectively are thermostated. However, as soon as a sample is taken, its temperature drops. This is the case in pipette-tip, filter and sampling tube methods etc.; energy (temperature) is constantly transferred to the sampling device. Eventually, the temperature of the samples will vary at different lower levels. As a result, a huge standard deviation can be seen in the dissolution charts. Furthermore, the amount of released active does not correspond with the measured value, since the saturation concentration depends on the temperature of the sample (Figure 1). Page 10

11 Taking a linear trend as a model, the error is caused by only a slight change in temperature. As soon as the temperature differs by merely 2 K, the analytical error is already at a level of 7.7% (Figure 2). Please remember, the specification limit of the Ph. Eur. allows temperature variations of ± 2 K for media in dissolution testing. In reality, however, the drop in temperature could easily achieve a level of K. FIGURE 2 ( S E T = T1 -S T2 ) (( x 37 C ) - ( x 35 C )) ( ) x 100 [%] = x 100 [%] = x 100 [%] = 7.7% S T1 ( x 37 C ) Error in the determination of solubility when temperature is not considered "...the pharmaceutical industry is not only facing new technologies. With [...] new kinds of dosage forms, analytical aspects have to be considered that were of minor importance in the past." Solution To gain reliable results, it is therefore indispensable to prevent any kind of temperature losses between sampling and final sample preparation. Good results can be achieved when all devices in contact with the liquid sample have been tempered in advance. Hereby, 42 C proved to be an ideal temperature, since all the devices start to cool down as soon as they are taken from the oven. Nevertheless, sampling, filtration and final sample preparation have to be carried out rapidly. With this approach, lowest standard deviations can be achieved. FIGURE 3 Flow diagram displaying the sampling procedure The flow diagram (Figure 3) shows how sampling takes place; the red frames indicate which devices should be pre-tempered. Acknowledgement The authors would like to thank Sarah Ganslmeier and Jonas Hilzendegen for their contributions and support during the practical part of this study. Page 11

12 TASTE MASKING determining the minimum amount of Kollicoat Smartseal 30 d formulation to be applied for taste-masking functionality Thorsten Agnese, Thorsten Cech INtrOduCtION In the field of functional film-coating, the coating level typically corresponds to the quality of the dissolution profile. Here, one has to differentiate between two principles: a) Functionality is strongly dependent on layer thickness (e.g. sustained release, moistureprotecting coatings). b) Functionality is not strongly dependent on layer thickness (e.g. gastric-resistant, tastemasking functionality). In the first example, functionality obeys Fick s first law (permeation), whereas the latter application mainly requires a homogeneous and completely closed coating. Variations in content uniformity lead directly to a high standard deviation in dissolution results. During development, but also within the realm of Quality by Design (QbD), it is therefore essential to know the exact coating level of a solid oral dosage form (SODF). Various analytical methods can be applied to determine the content of applied polymer or pigment onto a core [1, 2, 3]. However, such tests are either complex or costly, whereas easier methods to define the coating level by weight comparison or by color measurement might produce high standard deviations. The only reliable method is analytical detection only component (tracer) of the coating formulation [4]. Kollicoat Smartseal 30 D is one of the most recent polymers capable of delivering two functionalities: moisture protection and taste masking [5]. The aim of this investigation was to evaluate the coating level required to provide taste masking functionality. The investigation was carried out with two differently shaped tablets (round and oval). The caffeine-containing tablets were coated in small- and large-scale side-vented pan coaters (Perfima). Page 12 ExPErImENtAl methods Materials and formulations For the core formulation (Table 1), the following components were used: caffeine (gran ), Ludipress LCE, Kollidon CL-F, Kollidon VA64 fine (all BASF) and magnesium stearate (Baerlocher). For the coating formulation (Table 2), the following excipients were used: Kollicoat Smartseal 30 D and iron-oxide red (all BASF), triethyl citrate (Jungbunzlauer Ladenburg), butylenehydroxytoluene (BHT) (Sigma-Aldrich), talc (Merck). As colorant (tracer), FD&C Blue No. 1 (BASF) was used. table 1. Composition of the cores Ingredients Quantity [%] Caffeine, gran ludipress lce 74.0 Kollidon Cl-F 5.0 Kollidon VA64 fine 5.0 Mg stearate 0.5 table 2. Composition of the coating Ingredients Quantity [%] Kollicoat Smartseal 30 D Triethyl citrate 6.73 BHT 0.52 Talc Colorant 2.00 Indicating colorant 1.00 methods ANd EquIPmENt Coating process Round and oval tablets were coated. The dispersion was applied using the I.M.A. equipment Perfima Lab (with a medium drum 30l) and Perfima 200 (200l). table 3. Coater settings (process parameters) Parameters Perfima Lab Perfima 200 Batch size Round cores Oval cores 21.8 kg 20.2 kg kg kg Volume 30 l 200 l Drum speed 8 rpm 5 rpm Inlet air temperature 55 C 55 C Inlet air quantity 1,000 m 3 /h 2,80 m 3 /h Spray rate 45 g/min 180 g/min Process time: Round cores Oval cores 104 minutes 91 minutes 173 minutes 152 minutes All samples were stored for 4 hours at 60 C to make sure that the coating was perfectly formed. UV testing The UV/VIS spectrometer Agilent 8453 fitted with a 1 cm cuvette was used for the analytical tests. Tablets were dissolved in ml of solvent (depending on the amount of indicating colorant), passed through a 0.45 µm filter (Sterivex, Millipore) and then measured by UV/VIS. Dissolution testing For the dissolution test, standard equipment according to Ph. Eur. was used. As the taste masking functionality was to be realized in the oral cavity, phosphate buffer (ph 6.8) was used as a dissolution medium. The criterion for a fully functional coating was that no drug release was observed for a period of 2 hours. To increase the sensitivity of the test, 5 tablets were tested at the same time in one dissolution vessel.

13 Results and discussion The film-coating process with Kollicoat Smartseal was simple and was conducted without any problems. Even though there was no tendency for tackiness, moderate spray rates were chosen to achieve a high content uniformity of the applied coating. When using low spray rates, spray losses are certainly an issue in every film-coating process. In order to be able to interpret the results properly, the actual coating level of each sample was determined. In the dissolution diagrams shown below, both the theoretical and actual coating levels (the latter in brackets) are indicated. Bearing standard deviation in mind, it was interesting to see that neither scale nor tablet shape had any impact on the resulting spray losses (Figure 1). As a rule of thumb, about 10% spray losses could be considered typical. In order to obtain an effect on drug release, a coating level of just 1.5 to 2.5 mg/cm² had to be applied. Tablets with this amount of coating were found to show distinctly delayed drug release. At a coating level of 2.5 mg/cm², the first amounts of caffeine were detected at a dissolution time of about 20 minutes (Figures 2, 3, 4 and 5). This delay in drug release could well be sufficient for some applications. To ensure the core is completely and durably sealed, 3.5 mg/cm² of the Kollicoat Smartseal formulation had to be applied. At this coating level, no drug release at all was detected. Regarding uniformity of the applied coating, it would appear that the large-scale batches (Figures 3 and 5) yielded higher homogeneity. The trials conducted on a small scale delivered dissolution profiles indicating that individual tablets were not homogeneously coated (Figures 2 and 4). On a small scale, this effect was shown on the oval tablets in particular (Figure 4). However, a coating level of less than 4 mg/cm² still prevented the caffeine from being released. FIGURE 1 FIGURE 2 Caffeine release [ % ] Comparison of calculated and photometrically determined coating levels (mean ± s, n=5) Dissolution time [ minutes ] (oval) (oval) Perfima Lab Coater dissolution profiles (ph 6.8) of round tablets with different coating levels. Theoretical and (in brackets) analytically determined coating levels are indicated (mean: n=5). 0.0 (0.0) mg / cm (0.2) mg / cm (0.7) mg / cm (1.0) mg / cm (1.6) mg / cm (2.6) mg / cm (2.8) mg / cm (3.2) mg / cm (3.7) mg / cm (4.2) mg / cm (5.8) mg / cm 2 Page 13

14 FIGURE 3 Caffeine release [ % ] Dissolution time [ minutes ] 0.0 (0.0) mg / cm (0.4) mg / cm (0.9) mg / cm (1.3) mg / cm (1.8) mg / cm (2.1) mg / cm (2.6) mg / cm (3.0) mg / cm (3.7) mg / cm (4.6) mg / cm (5.1) mg / cm 2 Perfima 200 Coater dissolution profiles (ph 6.8) of round tablets with different coating levels. Theoretical and (in brackets) analytically determined coating levels are indicated (mean: n=5). Even though Kollicoat Smartseal is regarded as a functional polymer, it can be used for instantrelease application. This means that as soon as the tablet has been placed in an acidic environment (ph < 5.5), the polymer becomes readily soluble. This was indicated by its fast dissolution in acidic media (Figure 6). The coating level was found to have hardly any effect on dissolution time. Conclusion It could be seen that quite low coating levels of about mg/cm² already led to a distinctive reduction in drug release. For instance, at ph 6.8, a delay in drug release of 20 minutes was achieved at a coating level of 2.5 mg/cm². However, 3.5 mg/cm² had to be applied in order to seal the tablet durably. Furthermore, these film-coated tablets did not release any drug at all during the testing period of 2 hours. Nevertheless, as soon as the ph of the media was altered to 1.0, instant drug release was observed. Even with high coating levels of about 5 mg/cm², 100% drug release was found within 25 minutes. Most importantly, all the results were independent of tablet shape and batch size. FIGURE 4 Caffeine release [ % ] Dissolution time [ minutes ] 0.0 (0.0) mg / cm (0.4) mg / cm (0.8) mg / cm (1.4) mg / cm (1.8) mg / cm (2.2) mg / cm (2.5) mg / cm (2.9) mg / cm (3.3) mg / cm (3.9) mg / cm (5.3) mg / cm 2 Perfima Lab Coater dissolution profiles (ph 6.8) of oval tablets with different coating levels. Theoretical and (in brackets) analytically determined coating levels are indicated (mean: n=5). "Even though Kollicoat Smartseal is regarded as a functional polymer, it can be used for instant release appli cations." Acknowledgements The authors would like to thank Felicitas Guth for her contribution. In addition, we would like to thank IMA S.p.A. Active Division and in particular Caterina Funaro, Giusi Mondelli and Fiorenzo Cembali for their considerable technical support during the practical part of this study. Page 14

15 REFERENCES Caffeine release [ % ] Dissolution time [ minutes ] 0.0 (0.0) mg / cm (0.5) mg / cm (1.0) mg / cm (1.5) mg / cm (1.8) mg / cm (1.8) mg / cm (2.7) mg / cm (3.3) mg / cm (3.5) mg / cm (3.8) mg / cm (4.6) mg / cm 2 [1] Maclaren, D. D.; Hollenbeck, R. G. A highperformance liquid chromatographic method for the determination of the amount of hydroxypropyl methylcellulose applied to tablets during an aqueous film coating operations; Drug Development and Industrial Pharmacy, 1987, Vol. 13, No. 12, (pages ). [2] Harrison, J. J.; Lafferty, I.; Moore, W. D.; Rawlins, D. A.; Rissen, N. R.; Thwaites, P. M. Titanium determination as a method of quantifying film-coat application on to tablets; Drug Development and Industrial Pharmacy, 1991, Vol. 17, No. 1, (pages ). FIGURE 5 Perfima 200 Coater dissolution profiles (ph 6.8) of oval tablets with different coating levels. Theoretical and (in brackets) analytically determined coating levels are indicated (mean: n=5). [3] Kirsch, J. D.; Drennen, J. K. Determination of film-coated tablet parameters by near-infrared spectroscopy; Journal of Pharmaceutical and Biomedical Analysis, 1995, Vol. 13, No. 10, (pages ). Caffeine release [ % ] 0.5 (0.5) mg / cm (1.0) mg / cm (1.5) mg / cm (1.8) mg / cm (1.8) mg / cm (2.7) mg / cm (3.3) mg / cm (3.5) mg / cm (3.8) mg / cm (4.6) mg / cm 2 [4] Agnese, T.; Cech, T.; Guth, F. Developing a photometric method to determine the amount of film-coating material applied onto individual tablet cores; 3rd PharmSci- Fair; June 13-17, 2011; Prague, Czech Republic. [5] Kolter, K.; Guth, F.; Angel, M. Physicochemical characteristics of a new aqueous polymer; AAPS Annual Meeting and Exposition, November 14 18, 2010, New Orleans, Louisiana, U.S.A. Dissolution time [ minutes ] FIGURE 6 Perfima 200 Coater dissolution profiles (ph 1.0) of oval tablets with different coating levels. Theoretical and (in brackets) analytically determined coating levels are indicated (mean: n=3). Page 15

16 quality assurance EXCiPACT TM A new, voluntary international pharmaceutical excipients cgmp and cgdp certification scheme Tony Scott, Adviser European Fine Chemicals Group (EFCG) EXCiPACT is a new, voluntary international certification scheme designed and developed to assure cgmp and cgdp standards are being used in the manufacture and supply of pharmaceutical excipients. The scheme was launched in January The safety of medicines for patients is paramount to all: the pharmaceutical industry, suppliers of excipients, national and regional health care agencies and regulators. To assure the quality of medicines produced, risks in the supply chain need to be evaluated and minimized. Thousands of different excipients are used in medicines and make up, on average, about 90% of the volume or weight of each product. They represent a market value of approximately 3 billion, accounting for 0.5% of the total pharmaceutical market according to industry experts. However, few excipients are manufactured solely for pharmaceutical use. With legislation requiring cgmp and cgdp for excipients in Europe and the USA, excipient suppliers will be faced with an avalanche of quality audits and related requests to ensure their facilities and products meet these new requirements. Legislation for the USA already exists; it s now a matter of implementation. It can be argued that the Falsified Medicines Directive means legislation for Europe on these matters too. Excipient suppliers, distributors and the pharmaceutical industry are fully committed to controlling the use of high-quality excipients throughout the supply chain, and ensuring this by self-regulation. As a result, a group of industry experts from the European Fine Chemicals Group (EFCG), the International Pharmaceuticals Excipients Council (IPEC) Europe, IPEC Americas, the European Association of Chemicals Distributors (FECC) and the Pharmaceutical Quality Group (PQG) have worked together on the development of a certification scheme for pharmaceutical excipient suppliers called EXCiPACT. The EXCiPACT scheme provides independent certification of manufacturers and suppliers of pharmaceutical excipients as a means of ensuring patient safety through supplier quality, while minimizing the overall supply chain costs. Key EXCiPACT principles: International : a pharmaceutical excipient manufacturer s certification should have the same acceptance and value anywhere in the world Inclusivity : the scheme will provide quality standards and be applicable to all pharmaceutical excipients Accessibility : the scheme should be accessible from as many third-party auditing organizations as possible Evolution not revolution : builds upon existing best practices, guides and standards Simplicity : the overall scheme should be as simple as possible Key deliverables: cgmp and cgdp standards suitable for third-party auditing Definition of auditor competency Definition of training requirements for auditors Certification scheme rules for third-party audit organizations resulting in an EXCiPACT certificate All these parties are in agreement that an international pharmaceutical excipient current good manufacturing practice (cgmp) and current good distribution practice (cgdp) certification scheme is one of the tools which will help to ensure the quality and reliability of these key ingredients for medicinal products throughout the supply chain. Page 16

17 EXCiPACT development and launch The EXCiPACT cgmp and cgdp standards were made available for public and stakeholder review in All submitted comments have been reviewed and amendments made, allowing the standards to be published in January A pilot study using these standards to assess excipient suppliers will follow to validate the scheme. As the standards act as annexes to ISO 9001, and 17021, organizations already ISOcertified will find it very effective to extend their certifications to the EXCiPACT standards. Alternatively, suppliers who do not hold ISO 9001 certification will be able to obtain an equivalent certificate through the forthcoming US national standard (ANSI-NSF 363), which also uses the EXCiPACT GMP standard. All suppliers will, therefore, have the choice of which certification route to follow. In either case, the requirements will be the same. Auditor training began in mid-january and EX- CiPACT was officially launched on January 25, 2012 in Barcelona. Over 150 stakeholders representing designers, manufacturers, suppliers, distributors and users of pharmaceutical excipients, plus regulatory bodies and academia, gathered in Barcelona on January 25 for the launch event. They heard and interacted with speakers from the FDA, MHRA, BASF, Croda, Pfizer, SGS and Merck Millipore, and discussed the reasons for creating EXCiPACT and the benefits it can bring to supply chain security, cost saving and patient safety. Much emphasis was placed on the training and certification of third-party auditors to deliver the scheme. A new website, is available to help the pharmaceutical supply chain to learn "The EXCiPACT scheme provides independent certification of manufacturers and suppliers of pharmaceutical excipients as a means of ensuring patient safety through supplier quality, while minimizing the overall supply chain costs." more about the use and value of EXCiPACT. In addition to useful background information, the website provides access to EXCiPACT Standards, a brochure containing information and guidance on the certification process, plus auditor training requirements, training sessions and qualifications. Lists of approved third-party audit organizations, approved auditors and certified organizations will be added as they become available. Rx-360 and EXCiPACT have collaborated and have now implemented an agreement so that all Rx-360 audits assessing excipient suppliers use the EXCiPACT standards. For further information contact info@excipact.org Page 17

18 ibuprofen Ibuprofen DC 85 Production site transfer to meet current and future growth Kristina Bräunig Ibuprofen DC 85 is the unique, directly compressible ibuprofen composition by BASF that ensures continuous compression at high speed without sticking. The formula consists of 85% ibuprofen, formulated with additional monographed excipients. This ready-to-use formulation allows the manufacturing of tablets with a high API concentration and a reduced size. In addition, Ibuprofen DC 85 can also be mixed with additional excipients to achieve different concentrations and tablet sizes. By using our product, formulators are able to avoid process steps such as granulation or compaction and thereby reduce process cost and complexity. The advantages of Ibuprofen DC 85 especially for high-speed production have been demonstrated with many examples from our customers (see also the recent publication Assessing Tablet-Sticking Propensity in Pharmaceutical Technology, Volume 36, Issue 1, pp ). BASF has recently transferred the production of this successful product to meet growing demand and prepare for future growth. The new setup consolidates several production steps in one site. This measure reduces complexity throughout the value chain, further increasing the reliability of supply. The new production site meets current GMP and FDA requirements, and has an excellent inspection track record. A GMP certificate is available upon request. Regular production began in early 2012, after initial validation batches in Both the chemical and physical characteristics of the validation batches were tested to ensure equivalent product performance. Material from the validation batches was compressed on a highperformance tableting machine and the physical characteristics of the tablets were subsequently tested. This performance test on manufacturing-scale compression equipment has shown that product behavior is equivalent for both old and new manufacturing sites. All tablets showed "Both the chemical and physical characteristics of the validation batches were tested to ensure equivalent product performance for our customers." equivalent characteristics with respect to hardness, friability, disintegration and dissolution. At the same time, no differences in the analytical data were found the new production site delivers material of the same quality and fulfills the agreed specifications. All data related to the production relocation are summarized in an equivalency report, which is available upon request. If you would like to receive a sample or learn more about Ibuprofen DC 85 and how it can help you to save time and money, please contact your regional representative (see page 24). Page 18

19 News Colorcon and BASF announce collaboration to develop filmcoating applications using Kollicoat Smartseal 30 D Jan Bebber At the end of 2011, Colorcon and BASF announced collaboration based on BASF s latest coating innovation, Kollicoat Smartseal 30 D. After procuring Kollicoat Smartseal 30 D from BASF, customers now have the option of choosing a package from Colorcon that includes the polymer and a pre-formulated additive system. This system further simplifies the preparation of the coating dispersion by lowering the number of materials to be dispensed by 50%, reducing the time needed by almost 40%. Hence, customers can keep their in-house handling effort to a minimum. Colorcon refers to Kollicoat Smartseal 30 D as the best-in-class reverse enteric polymer for taste-masking, an appraisal representative of the great market appreciation received since its launch in late Kollicoat Smartseal 30 D is the first water-based dispersion with both taste-masking and moisture-barrier properties. It was developed to simplify and accelerate aqueous film coating operations. Its no-sticking properties creates new opportunities for formulating tablet, pellet and particle coatings. Kollicoat IR - approved by US food and drug administration (FDA) and JPE listing has already been announced Christian Becker, Jan Bebber Two important regulatory milestones have been achieved for BASF s third-generation instant release coating polymer, Kollicoat IR. In January 2012, Kollicoat IR received approval by the FDA. Being under registration in several drug applications, this first approval will facilitate all subsequent filings that include the Kollicoat IR polymer and related products. As a result, formulators formulators targeting the US market can now easily benefit from the ease of formulation, superor processability and processability and the resulting cost efficiency of Kollicoat IR, Kollicoat Protect and the Kollicoat IR Coating Systems. IIG listing in the FDA database is expected with the next regular update. In addition, the Japanese health authority announced in February that Kollicoat IR will also be listed in the next issue of the Japanese Pharmaceutical Excipients (JPE). Ph.Eur Macrogol poly(vinyl alcohol) grafted copolymer USP/NF Ethylene glycol and vinylalcohol graft copolymer JPE listing expected late Q PMDA (Japan) approved TGA (Australia) approved IIG listing expected Q Page 19

20 NEWS BASF opens new global laboratory to support topical pharmaceuticals John Giannone, Nigel Langley, Sofiya Yashchuk, Thomas Rosen BASF is excited to announce the opening of a new global application laboratory in our Tarrytown, NY Innovation Center, focusing on topical formulations for dermatology and veterinary markets. This new laboratory will focus on pharmaceutical liquid and semi-solid ingredients and formulations for BASF worldwide. Work will include basic research on skin irritation and allergy reactions to full formulations using novel BASF solubilizers and its broadened excipient portfolio. The laboratory will also support customers in developing new marketing concepts and solving formulation challenges. BASF has a long history as an innovator in the personal care industry. This core chemistry is the foundation of BASF s considerable expertise in liquid and semi-solid formulations for skin applications. Historically, this knowledge has not been widely applied by BASF to the pharmaceutical industry. With the integration of the Cognis pharmaceutical-grade excipients, BASF has increased its range of lipid-based emollients, surfactants, emulsifiers, gelling agents, waxes and solubilizers. The former Cognis pharmaceutical excipient portfolio now allows BASF to become a partner in human and animal dermatology, and topical, transdermal and liquid medicines. Due to BASF's significant experience in skincare formulations, we anticipate close collaboration between our topical pharmaceutical and personal care laboratories. The new global laboratory for topical formulations is in close proximity to our personal care laboratories at Tarrytown, NY and within a short drive of our beauty care solutions laboratories in Long Island, NY. Both personal care laboratories are at the forefront of skincare research and formulation. With the addition of a laboratory concentrating only on the unique needs of the pharmaceutical industry, BASF will be able to help our customers develop effective topical medicines using the existing broad expertise for semi-solid formulations. "This new laboratory will focus on pharmaceutical liquid and semi-solid ingredients and formulations for BASF worldwide." The new global laboratory will operate under the general leadership of Dr. Nigel Langley, Head of Technical Sales, Pharmaceutical Ingredients, US. Dr. Langley is very experienced in pharmaceutical requirements for topical formulations. Daily operations will be conducted by Dr. Sofiya Yashchuk, a former BASF Personal Care colleague who has moved to the pharmaceutical group. In addition to her experience in personal care, Dr. Yashchuk gained API development knowledge before joining BASF, which will help provide a deeper understanding of drug formulations. Over the next few months, BASF plans to collaborate with a select group of pharmaceutical innovators, generic manufacturers, and custom manufacturing, research and development organizations. Furthermore, this group will reach out to dermatologists and academics involved in key research areas like sensitive skin reactions, irritation and permeability. All efforts will be directed towards helping the pharmaceutical industry bring more effective topical formulations to market, thereby improving patient health and compliance. Page 20

21 News PeroXeal TM the recently introduced Kollidon packaging concept receives industry recognition Claudia Easterbrook In recent years, BASF researchers have been looking into new ways of improving and guaranteeing the highest possible quality standards for the company s excipients, in addition to improving and optimizing manufacturing. The main focus has been maintaining product quality during storage and use. The quality of excipients used for drug formulations has attracted much interest, especially as new suppliers emerge on the market place. As a result health authorities worldwide and all parties involved in manufacturing, supply and usage increased their focus on non-api ingredients. In 2011, BASF launched a solution that ensures product quality remains impeccable even over time: the new PeroXeal packaging concept. "With PeroXeal, BASF has set new standards for excipients in terms of formula stability and purity, helping its customers in the pharmaceuticals industry to achieve higher levels of patient safety," says Dr. Boris Jenniches, Head of Global Business Management PVP at BASF. "With this new packaging concept, we can significantly reduce peroxide values to a level comparable with that of naturally-based raw materials. This makes Kollidon a viable alternative to such materials." PeroXeal protects BASF's PVP-based excipients, marketed under the trade name Kollidon, from environmental influences, such as atmospheric oxygen. As a result, it positively influences product quality and characteristics. Thanks to PeroXeal, BASF can ensure that Kollidon exhibits more consistent performance and greater formulation stability, as well as a low peroxide content and increased product stability. For this reason BASF's Kollidon grades are suitable for oxygen-sensitive APIs. Over the next two years, we will complete the transition for most of our grades produced in Ludwigshafen and Minden. Within this time frame, we will continue to directly inform our customers of specific changes. "With this new packaging concept, we can significantly reduce peroxide values to a level comparable with that of naturallybased raw materials." For further questions, please feel free contact our global technical expert Dr. Bernhard Fussnegger (Bernhard.Fussnegger@basf.com). Kollicoat SR 30 D approved in Japan Christian Becker Kollicoat SR 30 D, BASF s versatile sustained release coating polymer, has been approved by the Japanese health authority. Next to the existing monographs and directly in other major regions, this new customer registration indicates the continuing recognition of this high performance excipient by formulators worldwide. USP/NF Polyvinyl acetate dispersion IIG Polyvinyl acetate Ph.EUR Poly(vinyl acetate) dispersion (30%) Page 21

22 BREAKING NEWS let s talk about innovation: brand new brochure from BASF Now available: BASF s new solubilizer compendium When it comes to developing new products and enhancing existing ones, BASF have long been setting standards in the industry. The new Let s talk about innovation brochure takes a closer look at what exactly makes the chemical company such a highly regarded pioneer. Readers can discover how BASF s dedication to continuous innovation helps its customers tap into new market opportunities. Plus, the publication provides a comprehensive overview of the innovative products BASF has launched in recent years highlighting groundbreaking excipients such as Soluplus or Kollicoat Smartseal 30 D, for example, which provide solutions to industry issues such as bioavailability enhancement, solubility or taste masking. All while maintaining the highest quality standards and meeting the strictest regulatory requirements. Interested? Download your copy at BASF s new solubilizer compendium is a mustread for anyone working with APIs that exhibit poor solubility and bioavailability. It signifies BASF s vast expertise in solubilization and bioavailabilty enhancement, and is the result of many years of research. The publication provides a valuable overview of all relevant BASF excipients (Kolliphor grades, Soluplus and selected Kollidon grades) and offers helpful advice on creating solid solutions and dispersions. What s more, it includes a chapter dedicated to high-throughput screening as a means of selecting the right excipient or combination of excipients for a poorly soluble API. Let s talk about innovation New solutions to solve unmet formulation needs Dr. Karl Kolter (left) and Dr. Thorsten Schmeller (right), two enablers in excipients Pharma Ingredients & Services. Welcome to more opportunities. Custom Synthesis Excipients Active Ingredients Visit to download the compendium as a PDF file or to request a free hard copy. Page 22