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TATABLETING →DIRECT COMPRESSION →
CO-PROCESSED LACTOSE echnical brochure MEGGLE co-processed hypromel ose lactose (4000 mPa∙s) for direct compression (DC): RetaLac® General information
Modified release applications continue to be a development In the hypromellose chemical structure diagram (shown below), strategy for the global pharmaceutical industry. Products nearing the substituent "R" may represent a hydrogen atom, or the patent expiration are candidates for product life-cycle manage- methoxy or hydroxypropyl functional groups, which when substi- ment using this approach; however, other benefits such as tuted onto the cellulose backbone, form the hypromellose structure. improved efficacy through more structured active pharmaceutical The degree of substitution as well as the molecular weight affect ingredient (API) release profiles, cost effective product manufacture, the physiochemical properties. To define the level of methoxy or and improved patient compliance exist. With various options hydroxypropyl degree of substitution, the major global pharma- available for API modified release delivery, hypromellose copoeias (Ph.Eur., USP-NF, and JP) differ with four defined hypro- (hydroxypropyl methylcellulose or HPMC) has historically been mellose species (1828, 2208, 2906, 2910), classified according the excipient of choice to form hydrophilic matrices [1]. The basic to their relative degree of substitution: the first two digits indicate
structure of the commonly known methyl and hydroxypropyl
the percentage of methoxy groups, while the subsequent two mixed ether of cellulose is illustrated in Figure 1.
digits represent the percentage of hydroxypropyl groups. Exacting limits for the degree of substitution have been established. In addition, there is a method to determine average chain length by evaluation of apparent viscosity. Hypromellose grade 2208, with a nominal viscosity of roughly 4000 mPa·s, may be regarded as a very frequently used grade in modified release formulation development and manufacture.
R = −H, −CH3, −CH2−CHOH−CH3 Figure 1: Basic chemical structure of hypromellose. The substituent R represents either a hydrogen atom, a methyl, or a hydroxypropyl group. The corresponding physicochemical properties are strongly affected by content and distribution of substitution, as well as the molecular weight (n). MEGGLE Co-processed lactose RetaLac® 03-21-2014 Although hypromellose offers broad flexibility in tailoring API RetaLac® is the first hypromellose/lactose-based, co-processed release due to differing substitution levels and molecular weights, excipient specifically designed for DC and dry granulation of processability is generally limited to traditional labour, time, and modified release formulations.
energy intensive wet granulation manufacturing methods.
While a binary composition, RetaLac® is monoparticulate in Direct compression (DC) is the prominent method in the pharma- structure, having hypromellose and lactose in each particle. It is ceutical industry. DC offers many benefits, including, but not characterized by superior functional performance such as limited to, enhanced chemical stability and cost containment [2].
improved flow and blendability. Additionally, due to its monopar- With requirements for increased functional performance (such as ticulate structure, RetaLac® possesses both plastic and brittle improved powder flow and content uniformity) growing steadily, fracture deformation characteristics, enhancing compactability new excipients are needed. Given the physical characteristics in DC compared to traditional wet granulated and physical that fine, fibered cellulose derivatives possess, it is not surprising admixtures of the parent ingredients.
that hypromellose does not satisfy every development or production need. Although hypromellose manufacturers have introduced API release is controlled predominately by diffusion through the improvements such as agglomeration, the material still exhibits hydrophilic matrix, and is most robust in the range of pH 1 to insufficient performance overall. Issues such as segregation, low 7.4. To minimize development time, API dissolution prediction as densities, poor powder flow, and reduced compactability limit a function of tablet geometry is possible. This is aided by RetaLac®'s its elegant use in DC applications.
dramatic improvement in wettability compared to HPMC alone or in traditional wet granulations and simple admixtures.
Recently, through a proprietary agglomeration process, a co-processed composition comprising hypromellose and lactose, offering suitable alternatives to overcome these limitations, was developed. Possessing enhanced functional performance, the new excipient offers characteristics desired in formulation development and manufacture and may be of significant interest to innovator and generic pharmaceutical companies.
MEGGLE Co-processed lactose RetaLac® 03-21-2014 Co-processed excipients are innovative, superior products exhibit-ing unique functional characteristics not achieved through simple blending. The following chart provides recommended areas of application. Areas of applicationCo-processed lactose Tablet (Modified release application) Direct compression (also for Dry granulation Preparation of aqueous Extrusion, spheronization multi-unit and mini tablets) HPMC formulations = Highly appropriate Regulatory & quality information
RetaLac® is produced in Germany under ISO 14001 certification. cGMP, according to the Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients and USP General – Direct compression of modified release formulations Information Chapter <1078>, is implemented for MEGGLE – Superior processability compared to corresponding wet granulated and physical admixture of parent ingredients – Meets compendial requirements MEGGLE invests considerably in raw material resource sustain- – Drug release kinetics are predominantly controlled by ability, production standards, efficiency and is actively engaged in environmental protection. Excipients meeting pharmaceutical – Unaffected by acidic conditions (between pH 1 and 7) standards is our first priority.
– Dissolution can be quantitatively predicted as a function of tablet geometry Both raw material monographs are harmonized between Ph.Eur., – Dual compaction mechanisms enhances compactability USP-NF, and JP. A type 4 Drug Master File (DMF) exists. An – Dramatic improvement in wettability compared to pure authorization letter is available upon request. Specifications and regulatory documents can be downloaded from: www.meggle-pharma.com. MEGGLE Co-processed lactose RetaLac® 03-21-2014 Particle size distribution (PSD)
Figure 2 shows typical laser diffraction particle size distribution
Due to the hypromellose content, RetaLac® shows a tendency to analysis for RetaLac®, MEGGLE´s co-processed hypromellose/ absorb moisture at elevated relative humidity, as shown by lactose excipient. Results show a typical d10, d50 and d90 of 55, dynamic vapor sorption (Figure 3). Interrestingly, the equivalent
125 and 260 μm, respectively.
physical admixture maintains a largely similar behaviour to RetaLac® (not shown).
Typical particle size distribution (Laser diffraction) Sorption isotherm (Dynamic vapor sorption at 20 °C) RetaLac® – co-processed grade Cumulative distribution Q3(x)/% Distribution density q3lg(x) Equilibrium moisture (%) Particle size (µm) Relative humidity (%) Sorption Desorption Figure 2: Typical cumulative PSD and distribution density of MEGGLE's co-processed excipient, RetaLac ®, with a typical d10, d50 and d90 of 55, 125 and 260 µm, respectively. Analyzed by Sympatec ®/Helos & Rodos laser Figure 3: Water-absorption-desorption isotherm (20 °C) of RetaLac ®. Water-uptake is mainly driven by diffraction particle size analyzer. hypromellose and proportional to the moisture of the surrounding atmosphere. Co-processed RetaLac ® and its corresponding physical admixture show a similar behavior. Analysis performed by SPSx-1µ moisture sorption test system. Batch-to-batch consistency for all lactose products can be attributed to MEGGLE's long history and experience in lactose manufacture, and broad technical expertise. Constant in-process and final product testing ensures consistency and quality.
MEGGLE Co-processed lactose RetaLac® 03-21-2014 Scanning electron micrograph (SEM)
MEGGLE's co-processed excipient, RetaLac®, appears as a white, SEM image of RetaLac® demonstrates agglomeration of crystalline or almost white, odorless powder, which is freely flowing and alpha-lactose monohydrate and fibrous hypromellose into porous, partially soluble in cold water. It comprises equal parts of hypro- spheroidal particles, desired for formulation development and mellose (type 2208, a.k.a. K-type) with a nominal viscosity of manufacture. The individual components, lactose and hypromellose, 4000 mPa·s, together with a milled alpha-lactose monohydrate cannot be separated by physical means. Flow and compaction grade, both of compendial quality. A specialized spray-agglom- properties of co-processed RetaLac® outperform the simple physical eration process generates textured, highly structured particles, binary in composition, and monoparticulate in nature with d50 in the range of many directly compressable excipients, 100 μm to 200 μm.
Figure 4: SEM image of RetaLac ® particles exhibits morphological properties desired for formulation development and manufacture. Hypromellose is agglomerated with crystalline alpha-lactose mono- hydrate resulting into a porous, spheroidal particle having excellent flow and compaction properties. MEGGLE Co-processed lactose RetaLac® 03-21-2014 Functional related characteristics
Powder flow
Flow is an important consideration in many prepara- Co-processed lactose grade RetaLac® tions as it may impact critical formulation attributes Volume flow rate (ml/s) like tablet weight uniformity as well as tablet production rates. Various methods are commonly used for quanti-fication: angle of repose, density derived factors, volume or/and mass flow, or flowability index using
a FlowRatex® [3]. For data see Figures 5 and 6.
Figure 5: Volume flow rate (ml/s) as a function of aperture size (mm diameter) for MEGGLE's co-processed RetaLac ® analyzed by a FlowRatex ®. Specific surface
While RetaLac® exhibits a rough, highly textured struc- Co-processed lactose ture, it exhibits a relatively low BET surface value Carr's index BET surface (Figure 6). Co-processing the parent ingredients reduces
specific surface values in comparison to the corres- ponding physical admixture within a factor of 0.5.
Figure 6: Typical powder functional values for co-processed RetaLac ®. All methods were performed according to compendial standards. BET surface area and pore volume measurements were performed by an instrumented Quantachrome Autosorb-3 (adsorbent Kr2, outgas time and temperature: 7 hrs at 50 °C, in vacuo). MEGGLE Co-processed lactose RetaLac® 03-21-2014 Drug release kinetics
Drug release kinetics The overall drug release mechanism of hypromellose-based pharmaceutical formulations strongly depends on composition, API solubility, excipient(s) and polymer(s) used, as well as tablet geometry [4]. Release profiles of three model APIs having different
solubilities were evaluated at varying initial drug loads (0 – 60 % * Addition of 1 % fumed silica theophylline, paracetamol and diprophylline) upon dissolution testing in two media, 0.1 M HCl and a phosphate buffer system Figure 7: Composition of investigated systems comprised of MEGGLE's co-processed lactose excipient RetaLac ® (Figure 7).
and the following drugs: theophylline, paracetamol and diprophylline. Tablet preparation (single-station tablet press Korsch; Berlin, using flat-faced punches) was performed by DC at comparable hardness (60 – 70 N), constant diameter (11.3 mm) and tablet height (2.4 mm). Drug release was analyzed using USP 35 dissolution Impact of initial drug content on absolute drug release is shown
apparatus (paddle method, 80 rpm, 37 °C; Sotax, Basel, Switzerland) in 900 mL 0.1 M HCl or phosphate for theophylline. A monotonic increase of absolute amounts of buffer, pH 7.4. All experiments were conducted in triplicate. drug is observed, independent of the dissolution medium
(Figure 8a).
Drug release profileImpact of initial drug contentAbsolute drug release (mg) Absolute drug release (mg) Phosphate buffer pH 7.4 Theophylline (%): 5 10 20 30 40 50 60 Figure 8a: Effects of the initial theophylline content (as indicated in the diagrams) on the absolute drug release from RetaLac ®-based tablets upon exposure to buffer systems 0.1 M HCl and phosphate buffer, pH 7.4 (Initial tablet height 2.4 mm and diameter 11.3 mm). MEGGLE Co-processed lactose RetaLac® 03-21-2014 Drug release profileImpact of initial drug contentRelative drug release (%) Relative drug release (%) Phosphate buffer pH 7.4 Theophylline (%): 5 10 20 30 40 50 60 Figure 8b: Effects of the initial theophylline content on the relative drug release from RetaLac ®-based tablets upon exposure to buffer system 0.1 M HCl and phosphate buffer, pH 7.4 (Initial tablet height 2.4 mm and diameter 11.3 mm). However, the impact of the initial drug content on relative drug
This effect is significantly less pronounced for paracetamol and release provides an insight into phenomena during drug dissoluti- diprophylline. A representative overview of absolute and relative on. Relative drug release decreases first and starts to increase release kinetics at various initial drug contents is depicted in again at drug loads of greater than 40 % theophylline. A possible Figures 9a and 9b.
explanation for this observed decrease could be that for poorly
water-soluble drugs, the amount within the tablet could exceed
the amount of dissolved drug, thus not being available for diffusion.
On the contrary, at higher drug loads (> 40 % theophylline)
porosity of the matrix increases, leading to increased absolute
drug transfers (Figure 8b).
MEGGLE Co-processed lactose RetaLac® 03-21-2014 Summary absolute release kinetics from RetaLac®-based tablets
Impact of initial drug content
Absolute drug release (mg) Absolute drug release (mg) Absolute drug release (mg) Initial drug content 10 % Initial drug content 20 % Initial drug content 30 % Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Absolute drug release (mg) Absolute drug release (mg) Absolute drug release (mg) Initial drug content 40 % Initial drug content 50 % Initial drug content 60 % Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Figure 9a: Effects of the type of drug (theophylline, paracetamol and diprophylline) on the absolute release kinetics from RetaLac ®-based tablets with different initial drug content upon exposure to 0.1 HCl buffer system (Initial tablet height: 2.4 mm and diameter 11.3 mm). In not all cases error bars are visible. Since the introduction of modified release formulations, sustainable complex numerical analysis taking additionally limited drug attempts have been made to theoretically predict drug release solubility into account, and (iii) an overly simplified early-time profiles [5]. The basic intent is to support rational development
approximation. There was a positive correlation of theory and and minimize excessive experimentation in practical formulation experimental data in all cases, allowing significant simplifications development efforts, and thus help reduce cost. For RetaLac®-based in predicting drug release design of RetaLac®, exclusively [6, 7].
tablets, various approaches of varying complexity have been
For the first time, a very simple approximation may be used for applied: (i) Fick's second law of diffusion of a cylindrical device quantitative prediction of design of hypromellose/lactose tablets was used as a predictive model, assuming uniform drug distribution, on the release of drugs exhibiting very different water solubility. radial and axial mass transport and perfect sink conditions. (ii) A The reason for this unexpected short cut may lie in the dramatic 10 MEGGLE Co-processed lactose RetaLac® 03-21-2014 Summary relative release kinetics from RetaLac®-based tablets
Impact of initial drug content
Relative drug release (%) Relative drug release (%) Relative drug release (%) Initial drug content 10 % Initial drug content 20 % Initial drug content 30 % Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Relative drug release (%) Relative drug release (%) Relative drug release (%) Initial drug content 40 % Initial drug content 50 % Initial drug content 60 % Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Diprophylline Paracetamol Theophyl ine Figure 9b: Effects of the type of drug (theophylline, paracetamol and diprophylline) on the relative release kinetics from RetaLac ®-based tablets with different initial drug content upon exposure to 0.1 HCl buffer system (Initial tablet height: 2.4 mm and diameter 11.3 mm). In not all cases error bars are visible. increase of wettability of hypromellose due to co-processing with lactose. High water content (primordial for drug mobility) is achieved within a relatively short period of time and remains "about constant," independent of drug load. This may be reflected in constant diffusivities. From a practical point of view, very simple
equations may be used for product optimization and reduction in
development time (Figure 10).
Figure 10: A simple approximation may be used to predict drug release of RetaLac ®-based formulations assuming cylindrical devices, where Mt stands for absolute cumulative amounts of drug released at time t and M∞ for absolute cumulative amounts of drug released at infinity. D denotes the diffusivity and R stands for the radius of the cylindrical tablet. Only radial diffusion is considered [6, 7]. MEGGLE Co-processed lactose RetaLac® 03-21-2014 11 Compendial requirements
Compendial requirement RetaLac® has been designed to enable DC of hypro- Uniformity of content of single-dose preparations mellose-based matrix formulations. However, various Initial drug loading (%) pharmacopoeias make specific demands on basic tablet properties, such as drug content uniformity, Drug content (mg) mass uniformity, or friability. RetaLac®-based formulations easily fulfill the criteria of Ph.Eur. with regard to drug content and tablet mass, independent from drug load. According to method of analysis "uniformity of content of single-dose prepara- tions (2.9.6.)", individual drug contents of ten tablets with an overall weight > 250 mg should be between 85 % and 115 % of the average content.
Results for RetaLac®-based formulations with different initial theophylline loads are shown in Figure 11 and
had been found in full conformity to compendial requirements. None of the samples showed an indi- vidual content outside of the 85/115 % requirement, while relative standard deviation (RSD) did not exceed 6.54 %.
number of tablets not conform Likewise, the test on "uniformity of mass of single-dose preparations" had been determined according to Ph.Eur. (2.9.5.) and should not exceed ± 5 % of the Figure 11: Individual results of the test "uniformity of content of single-dose preparations, Ph.Eur. (2.9.6.)". None of the samples mean tablet mass. The results of initial drug loads with initial drug load between 10 % and 60 % theophylline showed an individual value outside the 85/115 % drug content between 10 % and 60 % theophylline content indicated uniformity requirement. RSD did not exceed 6,54 %. conformity and no single drug load exceeded a RSD of 3 % (not shown). Finally, friability of tablets should not exceed 1 %. A gravimetric test showed maximum values not exceeding 0.5 % at maximum drug load of 60 % theophylline.
12 MEGGLE Co-processed lactose RetaLac® 03-21-2014 Flow through an orificeFlow time (sec) RetaLac® shows superior performance to physical admixture and wet granulated formulation. Co-processed excipients should exhibit superior performance in comparison to the corresponding physical admixture. In a model formulation containing propranolol HCl, RetaLac® was compared to a
physical admixture comprised of a special, agglomer-
ated DC-grade of hypromellose and a traditional
ethanol-based wet granulation process.
As powder flow is a primary function in DC, flow time Initial drug loading (%) was evaluated using a standardized funnel at various RetaLac® Physical admixture Wet granulation initial drug loadings. RetaLac®-based blends show the shortest flow times, followed by blends comprising a Figure 12: Effect of preparation method on the propanalol HCl powder/granules flow time. The wet granulated physical admixture. Interestingly, it was not possible form (only possible up to 10 % drug load) demonstrated slowest flow times, followed by the physical admixture and RetaLac ®. Flow time was measured using a standardized funnel. to supply wet-granulated preparations of drug loads higher than 10 % due to coarse granules exhibiting high weight and hardness variation. Flow time of V10 – V500 volume difference RetaLac®-based blends was not affected by increasing V10 – V500 (ml) drug loads (Figure 12).
To evaluate the impact of compactability and/or segregation on bulk pharmaceutical powder blends, a tap volumeter is often used. Powder blend volumes are measured after 10 and 500 taps (V10 and V500), respectively. A low V10 – V500 value may indicate less fluctuation in die filling and thus, more uniform tablet weight and hardness. Difference in volume is recom- mended to be below 20 ml. Physical admixture comprising hypromellose and lactose and the wet Initial drug loading (%) granulated form clearly outvalue RetaLac® in its RetaLac® Physical admixture Wet granulation V10 – V500 magnitudes, independent of the initial drug load. Granules from wet granulation were found in Figure 13: Effect of preparation method on the V10 – V500 volume difference of the powder/granules. between, showing slightly higher results than RetaLac® Compressability was measured with a tap volumeter. The apparent volumes were recorded after 10 and 500 taps (V10 – V500). RetaLac ®-based powder blends showed lowest V10 – V500 values. (Figure 13).
MEGGLE Co-processed lactose RetaLac® 03-21-2014 13 Processability of RetaLac® To ensure proper and predictable powder compaction, Compression forces maximum compression forces, as measured by upper Forces measured (N) and lower punch, as well as residual and ejection force, are routinely monitored. In general, constant forces, within certain limits are preferred during production operations [8]. If a formulation containing
10 % propranolol HCl is prepared by three different methods (RetaLac®-based, physical admixture and wet granulation) resulting powder blends show diverging performance on the tablet press. For RetaLac® and physical admixture, compaction forces are significantly lower compared to wet granulation. Wet granulation and physical admixture show an excessive fluctuation over time. However, co-processed RetaLac® performs consistently (Figure 14).
Upper punch Lower punch Max. residual force (N) Max. ejection force (N) Irrespective of the method of preparation and drug Processability of physical admixture load, all tablets exhibited friability values below 1 %. Compression forces All tablets produced at 10 % initial drug load exhibited Forces measured (N) similar results. Beyond 10 % drug loading, RetaLac® exhibits superior performance compared to the physical admixture (Figure 15).
3,5003,0002,5002,0001,5001,000 500 0 Upper punch Lower punch Max. residual force (N) Max. ejection force (N) Processability of wet granulation Compression forces Forces measured (N) Initial drug loading (%) Upper punch Lower punch Max. residual force (N) Max. ejection force (N) RetaLac® Physical admixture Wet granulation Figure 14: Maximum compression force measured by upper (purple), lower (mint green) punch and maximum Figure 15: Effect of preparation method on the friability of tablets based on lactose, hypromellose and residual (violet) and ejection (grass green) forces for tablets containing 10 % propranolol HCl prepared by three propranolol HCl at different initial drug loading. different methods. RetaLac ®-based tablets and physical admixture showed overall lowest values in force measurement compared to the wet granulated form. However, co-processed RetaLac ® performs most consistently. Cylindrical tablets were prepared by a single-punch tablet press (Korsch EK 0; Berlin) using flat-faced punches. 14 MEGGLE Co-processed lactose RetaLac® 03-21-2014 Figure 16: Composition of an example application Example formulation comprising MEGGLE´s co-processed hypromellose and Vitamin C in a sustained release formulation
lactose excipient RetaLac ® and Vitamin C. Tablet With RetaLac®, it is possible to achieve a simplified preparation was performed by DC (single-punch press sustained release of Vitamin C in excess of 80 % after Ascorbic acid 97 % Korsch EK 0; Berlin, using flat-faced punches with a diameter of 11.3 mm). 8 hours using DC. Flow and density of the powder appeared very good. Compaction force of 200 MPa resulted in a tablet hardness of approximately 100 N with a corresponding friability of 0.5 %. Compaction was performed on an eccentric tablet press using Example formulation round, flat punches with 11.3 mm in diameter (Figures 16 and 17).
Drug release (%)100 Figure 17: Relative drug release of Vitamin C from a RetaLac ®-based tablet in aqueous medium according to the monograph "Ascorbic acid tablets" (USP-NF). Tablet preparation was performed by DC, all trials were performed sixfold. Packaging and shelf life
Packaging and shelf life Packaging material complies with Regulation (EC) No. 1935/2004 and 21 CFR 174, 175, 176, 177 and 178. Stability tests have been performed according to 12 kg Carton box with PE-EVOH-PE inliner ICH guidelines and an ongoing stability program is Figure 18: Packaging and shelf life of MEGGLE's RetaLac ®. implemented. Figure 18 provides an overview about
packaging size and material, and product shelf life.
MEGGLE Co-processed lactose RetaLac® 03-21-2014 15 MEGGLE App:
[1] Colombo, P. (1993). Swelling-controlled release in hydrogel
matrices for oral route. Adv. Drug Deliv. Rev. 11: 37 – 57 [2] Shangraw, R. F. (1989). Compressed Tablets by Direct
Compression Granulation Pharmaceutical Dosage Forms. Tablets, Vol. 1, Marcel Dekker, USA, 2nd ed: 195 – 246 [3] FlowRatex® Instruction Manual (2010). 28452 Constellation
Road, Valencia, Ca. USA. [4] Siepmann, J., Streubel, A., Peppas, N. A. (2002). Under-
standing and predicting drug delivery from hydrophilic matrix tablets using the "sequential layer" model. Pharmaceutical Research 19: 306 – 314 [5] Blagoeva, R., and Nedev, A. (2006). Monolithic Controlled
Delivery Systems: Part II Basic Mathematical Models. Bioautomation 5: 106 – 117 [6] Siepmann, J., Karrout, Y., Gehrke, M., Penz, F. K., Siepmann,
F. (2013). Predicting drug release from HPMC/lactose tablets. Int. J. Pharm. 441: 826 – 834 [7] Siepmann, F. , Karrout, Y., Gehrke, M., Penz, F. K., Siepmann,
J. (2013). A Simple Mathematical Model Allowing for the MEGGLE Consultant Prediction of Drug Release from HPMC/lactose-based Controlled Release Matrix Tablets. Poster, AAPS [8] Bogda, M. J. (2007). Tablet Compression: Machine Theory,
Design, and Process Troubleshooting. Encyclopedia of Pharmaceutical Technology, Ed. Swarbrick J., informa health-care, New York, London: 3614 MEGGLE Group Wasserburg
Phone +49 8071 73 476 MEGGLE warrants that its products conform to MEGGLE's written specification and makes no other expressed BG Excipients & Technology
Fax +49 8071 73 320 or implied warrantees or representations. For any specific usage, the determination of suitability of use or application of MEGGLE products is the sole responsibility of the user. The determination of the use, application, Megglestrasse 6 –12 and compliance of this product with regard to any national, regional, or local laws and/or regulations is the sole responsibility of the user, and MEGGLE makes no representation with regards to same. Nothing herein shall be construed as a recommendation or license to use the product or any information that conflicts with any patent or intellectual property of MEGGLE or others and any such determination of use is the sole responsibility of the user. MEGGLE US 03-21-2014 Sai

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