Democratic frontrunner Hillary Clinton has announced her opposition to the historic Trans-Pacific Partnership deal that Washington sealed this week with 11 other Pacific Rim nations.

In an interview on Wednesday, Clinton said the agreement left many "unanswered questions".

"As of today, I am not in favour of what I have learned about it," she told public broadcaster PBS.

"I don't believe it's going to meet the high bar that I have set."

As America's top diplomat Clinton spent years selling the trade pact, criss-crossing Asia to promote its benefits to countries like Australia, New Zealand Japan and Vietnam.

The Republican National Committee pounced on her "flip flop", branding it a "case study in political expediency" and an example of why many Americans do not trust her.

She caught flak from her Democratic nomination rivals too, including former Maryland governor Martin O'Malley.

"Leadership isn't changing your position on the eve of debate," he tweeted, referring to next week's debut Democratic showdown. "It's standing up for the American worker, always."

Political shape-shifting can be dangerous for a candidate as it arouses suspicion about character, motive and political gain.

Her recent departures from White House doctrine have caught the eye of US President Barack Obama.

"I also think that there's a difference between running for president and being president," Obama told reporters this month after Clinton broke with him over Syria.

"If and when she's president, then she'll make those judgments.

"I think Hillary Clinton would be the first to say that when you're sitting in the seat that I'm sitting in the situation room, things look a little bit different, because she's been right there next to me."

Clinton has repeatedly stressed that she is not running for a third Obama term - or a third Bill Clinton term, for that matter.

But for the former first lady, senator, and secretary of state, the question remains how far she will go to set herself apart.