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neider et al.95,96 studied indomethacin (IM) and cyclisation reaction of branching enzyme. Ball
piroxicam activation by cogrinding with PVP in a mill with drug:HBCD ¼ 1:5 weight ratio was
cryogenic mill (6750 Freezer/Mill, Inc., Metuchen, considered. Grinding time was fixed in 2 h and
New Jersey). 1 g sample (PVP/drug mass/mass 150 rpm. Interestingly, DSC analysis revealed
ratio ranging from 0.1 to 0.8) was milled at an that glibenclamide melting point in the coground
impact frequency of 10 Hz alternating milling system was reduced of 5.48C respect to the native
periods of 2 min with 1 min cool-down period drug that melts at 170.18C. This was the proof that
(overall milling time spanned between 60 and the original crystalline drug was completely
78 min). The authors were interested in evaluat- disappeared in favour of nano-crystalline one.
ing the stabilisation action of PVP by comparing The authors verified that cogrinding increased
re-crystallisation kinetics relative to pure ground drug apparent solubility up to 12.4 mg/mL, being
drugs and to coground drugs. The necessity of native drug solubility equal to 0.3 mg/mL.
recurring to cryo-milling was dictated by the These examples clearly show that, apart from
impossibility of getting a complete amorphous by the specific energy supplied by the mill, key
simple drugs milling at room temperature in the factors for the attainment of drug activation are
absence of the stabilising carrier. They found that drug:carrier ratios >1:2 and good chemico-physi-
PVP exerts a good stabilising action on both drugs cal interactions between drug and carrier.
even if better results were evidenced for IM.
Obviously, for both drugs, PVP stabilising action
increased in reason of its content in the coground
In Vivo
mixture. Finally, they found that coground cryo-
milled IM dissolution was neatly improved with While previous section was focussed on the in vitro
respect that of the same mixture that did not evaluation of coground systems activation, this
undergo cryo-milling process. section shows the in vivo evidences of activation
and their relations with in vitro release tests.
Indeed, what is often desired is to get information
Cyclodextrins
about in vivo performance resorting to in vitro
For their chemical and physical peculiarities, behaviour. In order to rationalize the presenta-
cyclodextrins are widely used as stabilising agents tion, examples are subdivided according to drug
(carrier) in drug mechanochemical activation. pharmacological class.
Indeed, a, b, g and substituted cyclodextrins
can be used. For example, Miro et al.97 coground
Anti-Inflammatory Drug
gliquidone (hypoglycaemic agent) with hydroxy-
propyl-b-cyclodextrin (HPbCD) in 1:2 molar ratio. Perret and Venkatesh55 showed data referring to
DSC and XRPD analyses revealed that the an activated system composed by drug X (anti-
authors obtained a system showing a very small inflammatory, poorly water-soluble crystalline
content of original crystalline drug, being the drug drug) and crosslinked polyvinylpyrrolidone
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 11, NOVEMBER 2009
3980 COLOMBO, GRASSI, AND GRASSI
(PVPclm) in a weight weight ratio equal to 1:2. system reflects into a similar in vivo superiority
The system, once coground in a vibrational mill, as shown in Figure 8B. This figure reports drug X
was characterised by 40% amorphous drug and plasma concentration (humans) following oral
60% nanocrystalline drug (original crystalline administration of a 200 mg dose commercial
drug absent). Figure 8A clearly shows the better reference (open circles) and activated (filled
release performance of the activated system (filled circles) tablet made by the same activated system
circles) in comparison to that of an identical w/w tested in vitro (Fig. 8A). Not only the maximum
ratio drug-polymer physical mixture (open cir- blood concentration (Cmax) relative to the acti-
cles). While after about 10 min physical mixture vated system is approximately two times that of
yields to a release environment concentration just the reference, but the area under the curve (AUC)
below 2 mg/mL, the activated system concentra- relative to the activated system is approximately
tion is up to 8.5 mg/mL after about 50 s and then, 1.3 times that of the reference. It is, thus, evident
due to amorphous drug re-crystallisation, con- the consistent increase of drug X bioavailability.
centration decreases to 7.9 mg/mL. Interestingly, Magarotto and coworkers99 presented data
the evident in vitro superiority of the activated regarding the activation of nimesulide, a low
water soluble ( 100 mg/mL, pH 7.5, 378C,100
melting temperature 148.78C) nonsteroidal anti
inflammatory drug. Cogrinding, performed in a
vibrational mill using b-cyclodextrin (bCD) as
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