PARTIALLY PREGELATINISED MAIZE STARCHES FOR ORAL SOLID DOSAGE FORMS

Transcription

1 PARTIALLY PREGELATINISED MAIZE STARCHES FOR ORAL SOLID DOSAGE FORMS LYCATAB C Partially pregelatinised maize starch LYCATAB C - LM Low Moisture partially pregelatinised maize starch

2 LYCATAB C Partially pregelatinised maize starches for oral solid dosage forms LYCATAB C-LM C O N T E N T S Introduction.... page 2 Description, monographs.... page 4 Powder properties.... page 6 Applications.... page 9 Capsule filling.... page 10 Direct Compression.... page 15 Wet Granulation.... page 17 Conclusion.... page 19 Literature.... page 21 P A G E 1

3 Introduction P A G E 2

4 Introduction Native starch is a common excipient for tablet and capsule manufacture. Due to its limited flow properties, native starch often requires the use of additional excipients and production steps, such as granulation. Pregelatinised starches, obtained by a simple physical modification of starch, are also well established excipients. LYCATAB C, pregelatinised maize starch, is designed for pharmaceutical use in oral solid dosage forms.* LYCATAB C-LM is our low moisture grade. LYCATAB C has all the properties of a versatile excipient. It has been developed as filler for two-piece hard gelatin capsules, but also as diluent binder for direct compression and binder for wet granulation. LYCATAB C is a free-flowing and self-disintegrating powder, suitable for many applications. Excellent flow properties and an adapted bulk density allow homogenous filling of capsules. It also contains native starch which ensures a rapid disintegration and drug release. LYCATAB C-LM is designed as a specific capsule filler for moisture sensitive APIs, improving the stability of the formulation. Once again, like LYCATAB C it demonstrates well adapted properties for capsule filling. * ROQUETTE patents (EP / US ) P A G E 3

5 Description, monographs P A G E 4

6 Description, monographs LYCATAB C and LYCATAB C-LM are obtained by a physical modification of native maize starch through a unique production process. LYCATAB C-LM is additionally dried. Figure 1: SEM of Lycatab C, magnification approx. x 50 LYCATAB C and LYCATAB C-LM consist of both native and pregelatinised starch. They form a stable and non-friable matrix. This specific combination allows for rapid disintegration and therefore fast drug release from oral pharmaceutical preparations. LYCATAB C and LYCATAB C-LM meet all the requirements of the EP monograph Starch, Pregelatinised, the USP NF monograph Pregelatinized Starch and the IP monograph Pregelatinised Starch. LYCATAB C and LYCATAB C-LM are natural excipients of vegetable origin. They are compatible with most active substances. Figure 2: SEM of Lycatab C-LM, magnification approx. x 200 P A G E 5

7 Powder properties LYCATAB C and LYCATAB C-LM are white to off-white odourless powders with enhanced flow properties. LYCATAB C and LYCATAB C-LM are dispersible and partially soluble in cold water. P A G E 6

8 Powder properties Particle Size/Flowability/Density LYCATAB C and LYCATAB C-LM have a mean particle size of about 100µm, as is typically required in pharmaceutical production. Typical particle size distributions are shown in Figure 3. Both products are dust free (see table 1), resulting in a good powder flow. Dust is also a source of problems in pharmaceutical development and production. The density and powder flow of these pregelatinised starches are well adapted to its use as pharmaceutical excipient. Figure 3: Typical particle size distribution of LYCATAB C and LYCATAB C-LM Volume (%) LYCATAB C LYCATAB C-LM Particle diameter (µm) Table 1: Typical particle size distribution of LYCATAB C and LYCATAB C-LM LYCATAB C LYCATAB C-LM Native maize starch Dust Content (<30μm) 10% 10% 80% Table 2: powder properties of LYCATAB C and LYCATAB C-LM Bulk density Tapped density Flowability LYCATAB C Free flowing LYCATAB C-LM Free flowing P A G E 7

9 Powder properties Water content and sorption/ desorption Isotherms Pregelatinised starches are moderately hygroscopic substances, exhibiting the typical sigmoidal sorption isotherms of starch. The water content of LYCATAB C is in equilibrium with the air humidity under moderate climatic conditions. LYCATAB C-LM is additionally dried and therefore more hygroscopic. Specific storage conditions such as keeping it in the original and unopened packaging are requested in order to guarantee this low water content. Water content at equilibrium (%) Figure 4: Sorption and desorption isotherms of LYCATAB C and LYCATAB C-LM Relative humidity (%) LYCATAB C Sorption LYCATAB C Desorption LYCATAB C-LM Sorption LYCATAB C-LM Desorption P A G E 8

10 Powder properties The low water content in LYCATAB C-LM helps preserve the chemical stability of moisture sensitive API s. Free water, potentially affecting the stability of formulations, might be bound by the low moisture grade of starch. Table 3: powder properties of LYCATAB C and LYCATAB C-LM Water content Water activity (typical values) LYCATAB C 14% max 0.25 LYCATAB C-LM 7% max 0.08 P A G E 9

11 Applications LYCATAB C and LYCATAB C-LM are multifunctional excipients, suited to the majority of solid oral preparations. Due to their specific properties, these pregelatinised starches contribute to a simple production process and assure a rapid disintegration of the final formulation. Both could be used as a flow aid for powder blends, compounded for direct compression of tablets and as a binder for wet granulation. They are excellent and fully integrated excipients for hard gelatin capsules, adapted for a large range of drug substance concentrations. P A G E 10

12 Applications Capsule filling LYCATAB C and LYCATAB C-LM have been developed as cost-effective fillers and disintegration aids for hard gelatin capsules. Their physicochemical properties are therefore well suited to the requirements of ideal capsule fillers. Their powder physical properties are designed to obtain best results in industrial process using all types of equipment. Adapted Density and Particle Size Appropriate density is a necessary characteristic for good filler for solid dosage forms. The LYCATAB C and LYCATAB C-LM production process results in an adequate density for this application. Compared to native maize starch, LYCATAB C and LYCATAB C-LM have a lower bulk volume, allowing a more effective filling of capsules. Therefore the capsule size could even be reduced. The particle size distribution of LYCATAB C and LYCATAB C-LM aids mixing with the drug and easy plug-forming of the powder mixture. The low dust content of LYCATAB C and LYCATAB C-LM reduces powder losses and fall-out when transferring the plug. Volume consistency A particular advantage of LYCATAB C and LYCATAB C-LM is that they exhibit low volume reduction under tamping, resulting in a consistent processing performance. P A G E 11

13 Applications Figure 5 : Powder compressibility, measured with 100g samples in EP settling device Volume reduction (ml) LYCATAB C LYCATAB C-LM Native maize starch Fully pregelatinised starch Taps High compatibility with gelatine LYCATAB C and LYCATAB C-LM are fully compatible with gelatin. Capsule formulation with LYCATAB C and LYCATAB C-LM helps guarantee the quality and consistency of pharmaceutical capsules over their complete shelf live. Brittleness Resistance Storage tests of capsules filled with LYCATAB C at different humidities have indicated no drying of the capsule shell; the origin of the brittleness of capsules. The mechanical properties of filled capsules were not reduced when stored at relative humidity of 10% or more over two weeks. No Interaction with Gelatin LYCATAB C and by extension LYCATAB C-LM do not cause any chemical interaction or cross-linking with gelatin. These chemical interactions are known to occur in the presence of some excipients which have a detrimental effect on the dissolution of capsules. The storage of filled capsules at 40 C and 75% relative humidity over three months had no effect on the dissolution of capsules, or impair drug release. P A G E 12

14 Applications Good machinability The powder properties of LYCATAB C and LYCATAB C-LM are well adapted for easy machining. Industrial and pilot scale trials have proven the main advantages of LYCATAB C and LYCATAB C-LM: z Good plug forming z Fill weight uniformity of the capsules z Short disintegration time of filled capsules z Self-lubricating properties Trials were performed on two types of capsule filling machines: z LYCATAB C with a Bosch GKF 120 dosing disc machine, filling empty # 1 capsules (analysis after 15 min, under stabilised conditions) z LYCATAB C-LM with a Bonapace IN CAP dosing disc machine, filling empty #2 capsules. LYCATAB C and LYCATAB C-LM are fully integrated excipients for capsule filling. The standard deviation of the weight of filled capsules is low and the disintegration time is short. LYCATAB C and LYCATAB C-LM are self-lubricated powders and could be used without any addition of a lubricant under pilot and industrial scale conditions. Nevertheless, the recommended lubrication level for pure LYCATAB C is 0.2% Magnesium stearate. Lubrication helps achieve a better powder consolidation and improves weight uniformity. It does not impair the disintegration time of filled capsules. Due to the improved powder density, the disintegration potential of the starch particles is better used. Table 4: Results of placebo capsule filling trials LYCATAB C LYCATAB C with 0.2% Mg stereate LYCATAB C-LM Equipment Bosch GKF 120 Bosch GKF 120 Bonapace IN CAP Capsule size # 1 # 1 # 2 Mean filling weight (mg) Standard deviation (%) Disintegration time 5 min 00 s 3 min 40 s 3 min 32 s P A G E 13

15 Applications Superior disintegration properties and faster drug release LYCATAB C and LYCATAB C-LM have unique and optimised disintegrating properties, contributing to a high quality of pharmaceutical capsules. The nongelatinized starch granules of LYCATAB C and LYCATAB C-LM start to swell immediately in contact with water, leading to a rapid disintegration of the preparation. Furthermore, the low level of the cold-water soluble fraction (cold water solubility around 7% only) and the resulting low viscosity of LYCATAB C and LYCATAB C-LM contributes to a very fast penetration of water into the capsules and hence an accelerated disintegration. Dissolution studies of LYCATAB C in comparison with competitor s XX (partially pregelatinised starch - PPS) were conducted, using # 0 gelatin capsules filled with a blend of 75% of partially pregelatinised starch and 25% drug substance. Two different drugs, having different solubilities, have been selected as models: Propranolol chlorhydrate: soluble in water Acetaminophen: sparingly soluble in water Figure 6: Dissolution of Propranolol capsules at different ph values Propranolol dissolution rate (%) LYCATAB C ph 1,3 40 XX ph 1,3 LYCATAB C ph 4,7 20 XX ph 4,7 LYCATAB C ph 6,8 XX ph 6, Time (min) P A G E 14

16 Applications Figure 7 : Dissolution of Acetaminophen capsules at different ph values Acetaminophen dissolution rate (%) LYCATAB C ph 1,3 XX ph 1,3 LYCATAB C ph 5,8 XX ph 5, Time (min) Not all partially pregelatinised starches are equivalent with regards to drug dissolution rate. Compared to competitors, LYCATAB C exhibits a faster and higher dissolution rate for soluble drugs (example propranolol) and sparingly soluble drugs (example acetaminophen) over a wide ph range. These higher dissolution rates obtained with LYCATAB C are due to faster disintegration of the capsules. P A G E 15

17 Applications Direct compression LYCATAB C fulfils all critical functions required from direct compression excipients. LYCATAB C s unique composition of native and pregelatinised starch gives it dual functionality: disintegrant and binder. LYCATAB C s superior flow properties and its binding properties allow its use in tablet production as second DC filler. It could also improve the powder flow of the blends. Therefore it contributes to the weight uniformity and stable API content at industrial production speed. LYCATAB C only needs a low level of lubricant in direct compression. It also contributes to a reduction in ejection forces during tableting. It should be noted that the compactability of pregelatinised starch excipients (such as LYCATAB C when used as a sole DC binder) could be reduced by high ratios of Magnesium stearate, by too long mixing time, or non appropriate production conditions. A film layer of Mg- stearate could form on the powder surface, limiting its binding properties. A careful determination of production parameters and the appropriate choice of lubricant is recommended. A comparative study was performed on a rotary press (30 punches, 7 mm diameter, target tablet weight 100,0 mg) using following formula: Component Active pharmaceutical ingredient (API) Partially pregelatinised starch (Lycatab C or XX from competitor) Microcristalline Cellulose (DC grade) Sodium Stearyl Fumarate Amount/tablet 3.0% 48.5% 48.0% 0.5% The trials demonstrate the value of LYCATAB C in tablet formulations. P A G E 16

18 Applications Figure 8 : Compression profile of LYCATAB C and tablet disintegration compared to competitor s partially pregelatinised starch xx 100 Tablet disintegration time (s) Tablet hardness (N) LYCATAB 20 C XX from competitor LYCATAB C XX from competitor Compression force (kn) Tablet hardness (N) LYCATAB C with an adapted compactability ensures high tablet hardness at low compression forces, and a low friability. It is valuable second filler binder in DC formulations. LYCATAB C s superior disintegration properties allow simple formulations without the addition of another disintegrant. P A G E 17

19 Applications Wet granulation LYCATAB C, like all other pregelatinised starches, is partially soluble in cold water. It can therefore be employed as a binder-disintegrant in wet granulation, improving hardness and disintegration of tablets. The recommended application level is about 15% in the total formulation. A comparative study was performed with a DIOSNA high shear granulator using following formula: a- monohydrate lactose Microcrystalline cellulose (DC grade) Partially pregelatinised starch (LYCATAB C or competitor s XX ) Water 75% 10% 15% q.s. Granulation Studies: Trial 1 Competitor s XX Trial 2 LYCATAB C Same water quantity and granulation procedure were applied Trial 3 LYCATAB C 25% water quantity increase Same granulation procedure as for trials 1&2 To obtain granulates with a similar particle size, more water is required when granulating with LYCATAB C in comparison to XX from competitor. As a result, the drying step for the granulate is prolonged. These differences are due to their different production processes, resulting in different ratios of the cold water soluble fraction and the percentage of pregelatinised starch. LYCATAB C has a rather low, but very stable content of soluble fractions. LYCATAB C consists of controlled ratios of native and pregelatinised starch, resulting from a unique process. P A G E 18

20 Applications Any fluctuations in the cold water solubility and gelatinization level of pregelatinised starches have a direct impact of the needed water quantities for granulation. The granulates obtained from trials 1, 2 and 3, were lubricated with 0.3% Mg- stearate and then compressed on a single punch machine using concave 13mm punches. Figure 9 : Compression profiles of granulates obtained with LYCATAB C or with the partially pregelatinised starch xx and tablet disintegration times Trial 1 competitor s xx Trial 2 LYCATAB C, identical granulation conditions as with XX Trial 3 LYCATAB C, more water Tablet hardness (N) Tablet disintegration time (s) Trial n 1 Trial n 2 Trial n Compression force (kn) Trial n 1 Trial n 2 Trial n Tablet hardness (N) Tablets obtained from granulates with LYCATAB C and with competitor s XX as binder & disintegrant have similar hardness and cohesion. However tablets made of LYCATAB C disintegrate much faster (~40% faster), demonstrating the excellent disintegration properties of LYCATAB C. P A G E 19

21 Conclusion P A G E 20

22 Conclusion LYCATAB C and LYCATAB C-LM are partially pregelatinised maize starches complying with major pharmacopeial monographs. LYCATAB C and LYCATAB C-LM consist of both native and pregelatinised starch, and therefore act as both a binder and as an effective disintegrant. Good disintegration properties and low lubricant requirements make LYCATAB C the filler of choice for hard gelatin capsules, especially when using moisture sensitive API with the use of LYCATAB C-LM. LYCATAB C is also a highly effective binderdisintegrant in direct compression and wet granulation. LYCATAB C is a natural excipient with high versatility in the formulation of pharmaceutical products. P A G E 21

23 Literature P A G E 22

24 Literature 1.) Handbook of Pharm. Excipients, 7 th edition, Pharm. Press, London 2.) Häusler, O, Lefevre, Ph., Use of partially pregelatinised corn starch as filler for two piece hard gelatin capsules, Poster, 4 th World meeting on Pharmaceutics and Biopharm., 2002, c7d0fe.pdf 3.) Deepak, G. et al. Formulation and evaluation of Irbesartan immediate Release Tablets, International Research Journal of Pharmacy 2012, 3 (4), ) Jahn, T., Steffens, K.-J., Press chamber coating as external lubrication for high speed rotary press, Drug Dev. and Ind. Pharm., 2005, 31, ) Fechner, P.M. et al., Influence of water on Molecular and Morphological Structure of various Starches and Starch Derivatives, Starch, 2005, 57, P A G E 23

25 International technical support Roquette, one of the leading manufacturers offering starch derivatives and polyols, has developed a wide range of products and services especially dedicated to the pharmaceutical and cosmetic industries. Based on this experience, Roquette has been extending its range of starch excipients through technical innovation, while combining quality with performance. At Roquette, a team of pharmacists and development scientists, supported by a dedicated Application Development Center, are at your disposal for further information and assistance regarding the use of LYCATAB or other excipients from Roquette. Roquette Frères Lestrem cedex France Fax 33 (0) Telephone 33 (0) The information contained in this document is, to the best of our knowledge, true and accurate but all instructions, recommendations or suggestions are made without guarantee. Since the conditions of use are beyond our control, we disclaim any liability for loss and/or damage suffered from use of these data or suggestions. Furthermore, no liability is accepted if use of any product in accordance with these data or suggestions infringes any patent. No part of this document may be reproduced by any process without our prior written permission. Registered trademark of ROQUETTE Frères - Roquette Frères S.A./D3C - 09/2014 P A G E 24

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