Amorphization of
Pharmaceuticals by Co-
grinding with Neusilin®
Amorphization of crystalline drugs can be achieved In a previous report, we discussed solid dispersion through several methods. The most common method methods using Neusilin as an adsorption carrier to is melting and solidifi cation by rapid cooling over liquid improve dissolution and bioavailabilty of poorly water nitrogen or slow cooling at room temperature. Other soluble drugs. In this report, we present a much simpler methods for drug amorphization include milling, solvent method of co-grinding drugs with Neusilin to overcome evaporation, spray drying, and lyophilization. Solid state limitations to scale-up with solid dispersion methods. Poor amorphization can be achieved through high energy water solubility is a major bottle neck for the nearly 40% milling or co-grinding drugs with excipients leading to of new chemical entities (NCE's) launched world-wide and micronized particles with particle size distributions at co-grinding option with Neusilin is a welcome method to submicron levels. These amorphous forms are in a higher overcome this hurdle. energetic state compared to its crystalline counterpart The scope of this technical paper is not to cover the entire and therefore, provide an advantage in terms of solubility, pros and cons of co-grinding poorly water soluble drugs dissolution and bioavailability. Such amorphized forms of with excipients but to highlight the application of Neusilin, crystalline drugs leads to a marked improvement in their a synthetic form of Magnesium Aluminometasilicate as an dissolution rates and bioavailability. excipient for co-grinding. Table 1. Approaches to improve bioavailability of poorly water soluble drugs
Simple, Scalable, grinding with suitable Low temperature or cryo- grinding materials prevent re-crystallization required for faster amorphization Co-grinding / Milling Improves wettability, solubility, and temperature sensitive actives Improves stability Results in colloidal particles with small Degradation of API at higher Solid dispersion (Hot molten temperatures melt, Solvent evaporation, Improves wettability, solubility, Improves stability Co-grinding indomethacin with Neusilin US2 in the ratio 1:5 at 75% RH for 5 days at room temperature in a rolling jar mill consisting of a cylindrical porcelain jar and zirconia For practical formulation reasons, milling crystalline balls resulted in complete amorphization (Fig 1,2). drugs may be the easiest route to induce amorphization or transformations to other crystal polymorphs. Although milling can bring about particle size reduction or convert the crystalline state of a drug to amorphous state, stability Ball Milled l 1N5(Initial) of these formulations are at greater risk due to partial amorphization, milling temperatures, etc. Milling usually results in high energetic particles which tend to revert Ball Milled l 1N5(2 wk/40C/75/RH) back to crystalline forms unless high amount of surfactant or stabilizer is added to the formulation. These could in Ball Milled l 1N5(4 wk/40 C/75/RH) turn reduce the solubility and dissolution. Jet milling or ball milling can also introduce moisture which produces clumps in the mixture leading to handling problems and Co-grinding with excipients
Fig 2. XPD spectra of ball milled powder of indomethacin before and after storage up to 4 weeks at 40°C, 75% RH. Ref: Gupta et A number of successes have been reported by co- grinding crystalline drugs with excipients. The common excipients that have been used for co-grinding are polyvinylpyrrolidone, microcrystalline cellulose, Solubility and dissolution profi les were evaluated using cyclodextrins and various silicates including Neusilin. powders in a USP type II dissolution apparatus. Dissolution The examples of drugs that showed improvement in profi les of indomethacin co-ground with Neusilin US2 dissolution and or solubility drugs after co-grinding with initially and at 1 to 3 months of storage at 40°C/75% excipients include sulfathiazole, indomethacin, aspirin, RH showed a slight increase in the maximum transient ketoprofen, naproxen progesterone, glebenclamide and concentration (MTC) from the initial sample to the sample new chemical entities.
stored for 1 month. Further storage for 2 months did not Case studies
change the MTC. The maximum sustained concentration 1. Indomethacin with Neusilin® US2 2-6
(MSC) at the start was 13 times higher than the solubility Indomethacin is a non-steroidal anti-infl of crystalline indomethacin and increased with storage drug that reduces fever, pain and infl ammation. It is a crystalline and poorly water soluble drug and the rate of oral absorption is often controlled by the dissolution rate in -͠2( -͠2( -͠2( the gastrointestinal tract. Fig 3. Dissolution profi les (n=3) of indomethacin co-ground with Fig 1. Powder X-ray diffraction scans of a) crystalline indomethacin, Neusilin US2 (1:5 w/w) in O.1 N HCl (900 ml) : - initial; - 1 b) amorphous indomethacin (melt –quenched), c) amorphous month at 40°C, 75% RH, - 2 months at 40°C, 75% RH, - 3 indomethacin (co-ground at 75% RH with Neusilin US2 in the months at 40°C, 75% RH, - crystalline indomethacin. Ref: ratio 1:5 for 5 days), d) Neusilin US2. Ref: Bahl and Bogner, 2006 Bahl et al., 2008 Amorphous solids of Indomethacin co-ground with Neusilin corresponding liquid state.
US2 (1:4 and 1:5) at 75% RH was physically stable for 3 The amorphous co-ground mixture of aceclofenac and to 6 months when stored at 40°C and 75% RH. A further Neusilin was found physically stable during storage at investigation of pore volumes and pore diameters for 40°C/75% RH for up to 4 weeks (Fig 5). the initial and stored samples revealed no difference suggesting that there is no further deposition or depletion a. Aceclofenac Pure of drug from the pores of Neusilin US2 during storage.
b. Ace-Neu Mix (20 Hr)c. Ace-Neu 4 weeks 2. Aceclofenac with Neusilin® US2 1
Aceclofenac is a non-steroidal analgesic, antipyretic and anti-infl ammatory drug belonging to poorly water soluble BCS class II drug. Co-grinding aceclofenac with Neusilin® US2 in the ratio 1:5 at 25°C for 20 h using a modifi ed ball mill resulted in complete amorphization.
In vitro drug dissolution studies carried out for neat drug, Fig.5. XRD patterns of a. Aceclofencac, b. Ace-Neu mixture at 20 h and c. Ace-Neu mixture after four weeks storage at 40°C, 5 h and 20 h after co-grinding showed faster dissolution 75% RH. Ref: Vadher et al., 2009 rates when compared to crystalline aceclofenac. Co – ground mixture of aceclofenac / Neusilin US2 showed 103 XRD, DSC and FITR analysis confi rmed the amorphous % dissolution within 3 h when compared to 92% at the end state of aceclofenac after 4 week stability period with no reversion to crystalline state.
Ball milling of other drug candidates, ketoprofen and naproxen, both carboxylic acid containing drugs as well as progesterone which does not contain a proton donating group showed complete amorphization on milling with Aceclofneac PureAce-Neu Mix at 5hrs.
Ace-Neu Mix at 20 hrs.
0 15 30 45 60 80 100 120 150 180 240 300 360 420 480 It is believed that several potential interactions between the drug and surface of Neusilin makes the co-ground Fig 4. Dissolution profi le of Aceclofenac (pure drug) and co- mixtures physically stable during storage. pH could be ground mixture with Neusilin collected at 5 and 20 h interval. Ref: Vadher et al ., 2009 a major factor affecting the stability. Neusilin US2 is pH neutral when compared to other silicates and can have The initial drug dissolution rate was also faster with 20 h a broad range of compatibility. In case of slightly acidic co-ground sample than 5 h co-ground sample indicating drugs, co-grinding with alkaline grade of Neusilin like FL2 complete amorphization with extended grinding. The or FH2 will be the preferred choice. The FL2 and FH2 extended time could be related to the melting point of drug. Neusilin grades have a pH range of 8-10 and has been As a general rule when grinding at room temperature, found effi cient in maintaining stability of slightly acidic higher the melting point would require longer milling times. drugs like Quinapril hydrochloride 2. Amorphization can be done in less time if milling is carried Presence of silanol rings on the surface of Neusilin makes out well below the glass transition temperature (Tg) of the it a potential proton donor as well as proton acceptor. acceptor. Hydrogen bonding between silanols and drug as well as interaction between the drug and metal ions on the Neusilin can be successfully used to develop amorphous surface of Neuslin are suggested stabilizing mechanisms solids of crystalline poorly water soluble drugs by co- of indomethacin, aceclofenac and other carboxylic acid grinding methods. Amorphization leads to improved containing drugs.
solubility and dissolution times. Key advantages of incorporating Neusilin® US2:
Complete amorphization of crystalline poorly water soluble drugs is possible by co-grinding with Neusilin US2 Shorter amorphization time due to large surface area Amorphization leads to better dissolution and enhances bioavailability.
Process simple and scalable Physically stable and the amorphized drug do not revert back to crystalline forms.
1. Vadher AH, Parikh JR, Parikh RH, Solanki AB., by co-grinding with Neuslin US2: amorphization Preparation and characterization of co-grinded kinetics,physical stability and mechanism. Pharm mixtures of Aceclofenac and Neusilin US2 for Res. 23: 2317-2325, 2006 dissolution enhancement of Aceclofenac. AAPS 6. Gupta MK, Vanwert A, Bogner RH., Formation of physically stable amorphous drugs by milling with 2. Hailu SA, Bogner RH., Effect of pH grade of silicates Neusilin. J Pharm Sci. 92: 502-517, 2003 on chemical stability of co-ground amporphous The information found in this publication is presented in good faith quinapril hydrochloride and its stabilization using pH with no guarantee or obligation as to accuracy and no assumption modifi ers. J Pharm Sci. published online, 2009 of liability. Users should make their own tests to determine the suitability of these products for their own particular purposes. However, 3. Bhal D, Bogner RH., Amorphization alone does not because of numerous factors affecting results, Fuji Chemical Industry account for the enhancement of solubility of drug co- makes no warranty of any kind, express or implied, including those of merchantability and fitness for particular purpose other than the ground with silicate: the case of indomethacin. AAPS material conforms to its applicable current standard specifications. PharmSciTech. 9: 146-153, 2008 Statements concerning the use of the products or formulations described herein are not to be construed as recommending the 4. Bhal D, Hudak J, Bogner RH., Comparison of the infringement of any patent and seller assumes no liability for the ability of various pharmaceutical silicates to amorphize infringement arising out of such use.
and enhance dissolution of indomethacin upon co- grinding. Pharm Dev Tech. 13: 255-269, 2008 Neusilin is a trademark or registered trademark of Fu Neusilin is a trademark or registered trademark of F ji Chemical Industry Co.
y Co , Ltd. in Japan, ., Ltd. in Japan United States of America, , United States of America, 5. Bhal D, Bogner RH., Amorphization of indomethacin Europe and/or other countries.
Europe and/or other countries.

Source: http://www.fujichemical.co.jp/english/newsletter/images/1001/Fuji_Email%20Blast_Neusilin.pdf


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